Compounds that inhibit Mcl-1 protein

ABSTRACT

Provided herein are myeloid cell leukemia 1 protein (Mcl-1) inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula I, 
                         
or a stereoisomer thereof; and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds. The compounds and compositions provided herein may be used, for example, in the treatment of diseases or conditions, such as cancer.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/938,001, filed on Mar. 28, 2018, pending, which claims the benefit ofU.S. Provisional Application No. 62/479,171, filed on Mar. 30, 2017, andU.S. Provisional Application No. 62/479,230, filed on Mar. 30, 2017,each of which is hereby incorporated by reference in its entireties andfor all purposes as if fully set forth herein.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit myeloid cellleukemia 1 protein (Mcl-1, also abbreviated as MCl-1, MCL-1 or MCL1);methods of treating diseases or conditions, such as cancer, using thecompounds; and pharmaceutical compositions containing the compounds.

BACKGROUND OF THE INVENTION

One common characteristic of human cancer is overexpression of Mcl-1.Mcl-1 overexpression prevents cancer cells from undergoing programmedcell death (apoptosis), allowing the cells to survive despite widespreadgenetic damage.

Mcl-1 is a member of the Bcl-2 family of proteins. The Bcl-2 familyincludes pro-apoptotic members (such as BAX and BAK) which, uponactivation, form a homo-oligomer in the outer mitochondrial membranethat leads to pore formation and the escape of mitochondrial contents, astep in triggering apoptosis. Antiapoptotic members of the Bcl-2 family(such as Bcl-2, Bcl-XL, and Mcl-1) block the activity of BAX and BAK.Other proteins (such as BID, BIM, BIK, and BAD) exhibit additionalregulatory functions.

Research has shown that Mcl-1 inhibitors can be useful for the treatmentof cancers. MCl-1 is overexpressed in numerous cancers. See Beroukhim etal. (2010) Nature 463, 899-90. Cancer cells containing amplificationssurrounding the Mcl-1 and Bcl-2-1-1 anti-apoptotic genes depend on theexpression of these genes for survival. Beroukhim et al. Mcl-1 is arelevant target for the re-iniation of apoptosis in numerous cancercells. See G. Lessene, P. Czabotar and P. Colman, Nat. Rev. Drug.Discov., 2008, 7, 989-1000; C. Akgul Cell. Mol. Life Sci. Vol. 66, 2009;and Arthur M. Mandelin I I, Richard M. Pope, Expert Opin. Ther. Targets(2007) 11(3):363-373.

New compositions and methods for preparing and formulating Mcl-1inhibitors would be useful.

SUMMARY OF THE INVENTION

In one aspect, the present invention comprises a compound of Formula I:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable salt of the stereoisomer thereof,wherein:

Z is C or N;

Q is O, S, CR^(WA)R^(WB), or NR^(a)R^(b);

W is CR^(WA)R^(WB), —C═O, or is absent;

R^(WA) and R^(WB) are independently selected from H, —C₁₋₃alkyl,—C₂₋₃alkenyl, —C₂₋₃alkynyl, halo, —OH, or —O—C₁₋₃alkyl;

b, represented by the symbol

is a single or double chemical bond which may be cis or trans;

R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl,C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a),or —C(═O)NR^(a)R^(b);

R² is selected from H, halo, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkenylene, —C₁₋₆alkyl-O—C₁₋₆alkyl,—(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl orheterocycloalkyl group have 1, 2, 3 or 4 heteroatoms independentlyselected from O, N or S, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═Ogroup, and further wherein the spiroheterocycloalkyl, andheterocycloalkyl groups may include a S═O or SO₂;

R³ is selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆alkenyl,—(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b);

each of R^(2B), R^(2C), R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selectedfrom H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6-to 12-membered arylor heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

alternatively R³ and R⁴ together with the atoms to which they are bondedmay form a 5- to 12-membered ring, optionally containing a heteroatomselected from a N, O or S atom, in addition to the S and N atoms presentin the ring, wherein the ring may optionally contain at least one doublebond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A)substituents;

wherein R^(3A) is selected from H, halo, —OH, C₁₋₆haloalkyl, C₁₋₆alkyl,O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a),—SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or—C(═O)NR^(a)R^(b);

each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independentlyselected from H, OH, halo, or —C₁₋₆alkyl;

R^(7A) and R^(8A) are absent when b is a double chemical bond;

alternatively R⁷ and R⁸ together with the atoms to which they are bondedmay form a 3- to 12-membered ring, wherein the ring may optionallycontain at least one double bond;

R⁹ is independently selected from H, OH, —(═O), —C₁₋₆haloalkyl,—C₁₋₆alkyl, —C₁₋₆alkenylene, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, cyano, a 6- to12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl or heterocycloalkyl groups have 1, 2, 3 or 4heteroatoms independently selected from O, N or S, and the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group mayinclude a C═O group, and further wherein the spiroheterocycloalkyl, andheterocycloalkyl groups may include a S═O or SO₂;

R^(9A) is independently selected from H, —OH, halo, cyano,—C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,—C₁₋₆alkenylene, —(CH₂CH₂O)_(n)R^(a), —P(═O)OR^(a)OR^(b), —CSR^(a),—CS(═O)R^(a), —SR^(a), —SOR^(a), —OSO₂R^(a), —SO₂R^(a),—(CH₂CH₂O)_(n)CH₃, —(═O), —C(═O), —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(b), —CH₂—NR^(a)R^(b), —NR^(a)R^(b),—C₁₋₆alkyl-O—C₁₋₆alkyl, —OC₁₋₆alkyl, —O—C₁₋₆alkyl-O—C₁₋₆alkyl, phenyl, a6- to 12-membered aryl, a 6-to 12-membered heteroaryl, a 5- to12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyland heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independentlyselected from O, N or S, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, and heterocycloalkyl groups may contain a doublebond and may contain a C═O group, and further wherein thespiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O orSO₂;

wherein R^(9A) is not H when W is absent;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl,spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A)substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰substituents independently selected from OH, halo, —NR^(c)R^(d),—C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN,—C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-memberedspirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-memberedcycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, ora 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group,wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkylgroups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, Nor S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl,and heterocycloalkyl groups may include a C═O group, and further whereinthe spiroheterocycloalkyl and heterocycloalkyl groups may include a S═Oor SO₂;

alternatively R⁷ and R^(9A) together with the atoms to which they arebonded may form a 3- to 12-membered ring, wherein the ring mayoptionally contain at least one double bond;

alternatively R⁹ and R^(9A) together with Q, W, and the C to which W andQ are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring,optionally containing a heteroatom in addition to Q that is selectedfrom N, O or S, wherein the ring may contain a double bond, wherein thering may optionally include a C═O group, and further wherein the ringoptionally may be substituted by 1, 2, or 3 R¹¹ substituents;

R¹¹ is independently selected from H, —OH, halo, —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl,—O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —NR^(c)R^(d), —C(═O)NR^(c)R^(d),—C(═O)R^(c), —OC(═O)R^(c), —C(═O)OR^(c), a 6- to 12-membered aryl orheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3 or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroup may include a double bond, and wherein the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group mayinclude a C═O group, and further wherein the spiroheterocycloalkyl, andheterocycloalkyl groups may include a S═O or SO₂;

wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and the —OC₁₋₆alkyl ofany of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(4A), R^(5A),R^(6A), R^(7A), R^(8A), R^(9A), R^(WA) and R^(WB) substituents isunsubstituted or substituted by 1, 2 or 3 R¹² substituents independentlyselected from OH, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, halo,—O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b), —(NR^(a)R^(b)R^(c))_(n),—OSO₂R^(a), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, —(═O), —C(═O), —C(═O)R^(a),—OC(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —O—SiR^(a)R^(b)R^(c),—SiR^(a)R^(b)R^(c), —O-(3- to 10-membered heterocycloakyl), a 6- to12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O orSO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl,spirocycloalkyl and spiroheterocycloalkyl group of any of the R², R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R^(9A), R¹⁰, R¹¹, R¹², R^(WA) and R^(WB)substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R¹³substituents independently selected from OH, halo, —NR^(c)R^(d),—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl,C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d),—C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl orheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl, and heterocycloalkyl groups of R¹³ have 1, 2, 3or 4 heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl groups of R¹³ orthe heterocycloalkyl group of R¹³ may include a C═O group, and furtherwherein the spiroheterocycloalkyl and heterocycloalkyl groups mayinclude a S═O or SO₂;

wherein each R^(a), R^(b), R^(c), and R^(d) is independently hydrogen,OH, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴,—NR¹⁴R¹⁴, —SO₂R¹⁴, —(CH₂CH₂O)_(n)CH₃, —(═O), —C(═O)R¹⁴, —OC(═O)R¹⁴,—C(═O)OR¹⁴, —C(═O)NR¹⁴R¹⁴, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, benzyl, phenyl, —C₁₋₆alkyl-C(═O)OH,—C₁₋₆alkyl-C(═O)—O—C₁₋₆alkyl, —C₁₋₆alkyl-cycloalkyl,—C₁₋₆alkyl-heterocycloalkyl, —C₁₋₆alkyl-6- to 10-membered aryl,—C₁₋₆alkyl-6- to 10-membered heteroaryl, a 6- to 12-membered aryl orheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, where the heteroaryl,spiroheterocycloalkyl, heterocycloalkyl group or the—C₁₋₆alkyl-heterocycloalkyl groups have 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S, and the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, group ofR^(a), R^(b), R^(c), and R^(d) or the heterocycloalkyl group or the—C₁₋₆alkyl-heterocycloalkyl group may include a double bond and maycontain a C═O group, and the spiroheterocycloalkyl, or heterocycloalkylmay include a S═O or SO₂;

the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl,cycloalkyl, or heterocycloalkyl group of R^(a), R^(b), R^(c), and R^(d)and the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl groupof R^(a), R^(b), R^(c), and R^(d) can be unsubstituted or substitutedwith 1, 2, 3, or 4 R¹⁴ substituents, wherein each R¹⁴ is independentlyselected from H, —OH, —N═N=N, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl,—OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl,phenyl, tolyl, —C(═O)C₁₋₆alkyl, —C(═O)O—C₁₋₆alkyl, N(CH₃)₂ or—SO₂—N(CH₃)₂; and

wherein n is independently in each instance an integer of 1, 2, 3 or 4.

In another aspect, the present invention comprises a compound of FormulaI′:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable salt of the stereoisomer thereof,wherein:

Z is C or N;

Q is O or S;

W is CR^(WA)R^(WB) or C═O;

R^(WA) and R^(WB) are independently selected from H, C₁₋₃alkyl, halo,—OH, or —O—C₁₋₃alkyl;

b, represented by the symbol

is a single or double chemical bond which may be cis or trans;

R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl,—(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), or—C(═O)NR^(a)R^(b);

R² is selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a),—C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or —C(═O)NR^(a)R^(b),

R³ is independently selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or—C(═O)NR^(a)R^(b);

each of R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selected from H, halo,—C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6-to 12-membered arylor heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

alternatively R³ and R⁴ together with the atoms to which they are bondedmay form a 5- to 12-membered ring, optionally containing a heteroatomselected from a N, O or S atom, in addition to the S and N atoms presentin the ring, wherein the ring may optionally contain at least one doublebond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A)substituents;

R^(3A) is independently selected from H, halo, —OH, C₁₋₆haloalkyl,C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—C(═O)NR^(a)R^(b);

each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independentlyselected from H, OH, halo, —C₁₋₆alkyl;

R^(7A) and R^(8A) are absent when b is a double chemical bond;

R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

R^(9A) is independently selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N=N,—C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-memberedheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl,spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A)substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰substituents independently selected from OH, halo, —NR^(c)R^(d),—C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN,—C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-memberedspirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-memberedcycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, ora 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group,wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkylgroups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, Nor S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl,and heterocycloalkyl groups may include a C═O group, and further whereinthe spiroheterocycloalkyl and heterocycloalkyl groups may include a S═Oor SO₂;

alternatively R⁹ and R^(9A) together with Q, W, and the C to which W andQ are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring,optionally containing a heteroatom in addition to Q that is selectedfrom N, O or S, wherein the ring may contain a double bond, wherein thering may optionally include a C═O group, and further wherein the ringoptionally may be substituted by 1, 2, or 3 R¹¹ substituents;

R¹¹ is independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl,—O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c),—OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 6-to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl,and heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independentlyselected from O, N or S, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═Ogroup, and further wherein the spiroheterocycloalkyl andheterocycloalkyl groups may include a S═O or SO₂;

wherein the —C₁₋₆alkyl of any of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹, R^(4A), R^(5A), R^(6A), R^(7A), R^(8A), and R^(9A) substituentsis unsubstituted or substituted by 1, 2 or 3 R¹² substituentsindependently selected from OH, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,halo, —O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b), —(NR^(a)R^(b)R^(c))_(n),—SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O), —C(═O)R^(a), —OC(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —O—SiR^(a)R^(b)R^(c), —O-(3- to12-membered heterocycloakyl), phenyl, a 6-to 12-membered aryl orheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl,spirocycloalkyl and spiroheterocycloalkyl groups of any of the R², R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² substituents can be unsubstitutedor substituted with 1, 2, 3 or 4 R¹³ substituents independently selectedfrom OH, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c),—NR^(c)R^(d), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a),—C(═O)OR^(c), —B(OH)₂, a 6-to 12-membered aryl or heteroaryl, a 5- to12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl,and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independentlyselected from O, N or S, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═Ogroup, and further wherein the spiroheterocycloalkyl andheterocycloalkyl groups may include a S═O or SO₂;

wherein each R^(a), R^(b), R^(c), and R^(d) is independently H, OH,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴, NR¹⁴R¹⁴,—SO₂R¹⁴, —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O)R¹⁴, —OC(═O)R¹⁴, —C(═O)OR¹⁴,—C(═O)NR¹⁴R¹⁴, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—C₁₋₆alkyl-OH, benzyl, phenyl, a —C₁₋₆alkyl-3- to 12-memberedheterocycloalkyl, a 6- to 12-membered aryl or heteroaryl, a 5-to12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl,and heterocycloalkyl groups and the heterocycloalkyl group of the—C₁₋₆alkyl-heterocycloalkyl group have 1, 2, 3, or 4 heteroatomsindependently selected from O, N or S, wherein the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, and theheterocycloalkyl groups of the —C₁₋₆alkyl-heterocycloalkyl group mayinclude a C═O group, and further wherein the spiroheterocycloalkyl andheterocycloalkyl groups may include a S═O or SO₂;

the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl,cycloalkyl, heterocycloalkyl and the heterocycloalkyl groups of the—C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) canbe unsubstituted or substituted with 1, 2, 3, or 4 R¹⁴ substituentsindependently selected from H, OH, —N═N=N, halo, —C₁₋₆alkyl,—OC₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, phenyl, tolyl,—C(O)C₁₋₆alkyl, —C(O)OCH₃, SO₂-phenyl, or —SO₂—N(CH₃)₂; and

n is independently, in each instance, an integer of 1, 2, 3 or 4.

In another aspect, the compound of Formula I′ has Formula II′a:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

Another aspect of the present invention provides a pharmaceuticalcomposition that includes the compound of any of the embodiments or thepharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent.

Another aspect of the present invention provides a method of treatingcancer. Such methods include: administering to a patient in need thereofa therapeutically effective amount of the compound of any of theembodiments or a pharmaceutically acceptable salt thereof. In some suchmethods, the cancer is a hematologic malignancy. In some such methods,the cancer is selected from the group consisting of breast cancer,colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer,lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin'slymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenousleukemia. In some other such methods, the cancer is multiple myeloma. Insome other such methods, the cancer is acute myelogenous leukemia. Insome other such methods, the cancer is non-Hodgkin's lymphoma. Inanother aspect, the method further includes administering to a patientin need thereof a therapeutically effective amount of an additionalpharmaceutically active compound. For example, in some such methods theadditional pharmaceutically active compound is carfilzomib. In others,the additional pharmaceutically active compound is venetoclax. In stillother such methods, the additional pharmaceutically active compound iscytarabine.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Methods and materials aredescribed herein for use in the present disclosure; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the disclosure will be apparent fromthe following detailed description and figures, and from the Claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 demonstrates the superior in vivo efficacy of Example 1 relativeto Reference Compound 1 in a tumor PD model. Both compounds were dosedorally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 2 demonstrates the superior in vivo efficacy of Example 2 andExample 3 relative to Reference Compound 1 in a tumor PD model. Bothcompounds were dosed orally to female athymic nude mice inoculated withOPM-2 Luc cells.

FIG. 3 demonstrates the superior in vivo efficacy of Example 4 relativeto Reference Compound 1 in a tumor PD model. Both compounds were dosedorally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 4 demonstrates the superior in vivo efficacy of Example 10 relativeto Reference Compound 1 in a tumor PD model. Both compounds were dosedorally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 5 demonstrates the superior in vivo efficacy of Example 11 relativeto Reference Compound 1 in a tumor PD model. Both compounds were dosedorally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 6 demonstrates the superior in vivo efficacy of Example 13 andExample 14 relative to Reference Compound 1 in a tumor PD model. Bothcompounds were dosed orally to female athymic nude mice inoculated withOPM-2 Luc cells.

FIG. 7 demonstrates the superior in vivo efficacy of Example 18 relativeto Reference Compound 1 in a tumor PD model. Both compounds were dosedorally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 8 demonstrates in vivo efficacy of Example 1 in an OPM-2 xenograftefficacy model. Example 1 was dosed orally to female athymic nude miceinoculated with OPM-2 Luc cells.

FIG. 9 demonstrates in vivo efficacy of Example 4 in an OPM-2 xenograftefficacy model. Example 1 was dosed orally to female athymic nude miceinoculated with OPM-2 Luc cells.

FIG. 10 demonstrates in vivo efficacy of Example 10 in an OPM-2xenograft efficacy model. Example 1 was dosed orally to female athymicnude mice inoculated with OPM-2 Luc cells.

FIG. 11 demonstrates in vivo efficacy of Example 11 in an OPM-2xenograft efficacy model. Example 1 was dosed orally to female athymicnude mice inoculated with OPM-2 Luc cells.

FIG. 12 demonstrates in vivo efficacy of Example 13 in an OPM-2xenograft efficacy model. Example 1 was dosed orally to female athymicnude mice inoculated with OPM-2 Luc cells.

FIG. 13 demonstrates in vivo efficacy of Example 18 in an OPM-2xenograft efficacy model. Example 1 was dosed orally to female athymicnude mice inoculated with OPM-2 Luc cells.

DETAILED DESCRIPTION

The symbol “-” represents a covalent bond and can also be used in aradical group to indicate the point of attachment to another group. Inchemical structures, the symbol - is commonly used to represent a methylgroup in a molecule.

As used herein, chemical structures which contain one or more

stereocenters depicted with dashed and bold bonds (i.e.,

and

) are meant to indicate absolute stereochemistry of the stereocenter(s)present in the chemical structure. As used herein, bonds symbolized by asimple line do not indicate a stereo-preference. Unless otherwiseindicated to the contrary, chemical structures that include one or morestereocenters which are illustrated herein without indicating absoluteor relative stereochemistry encompass all possible stereoisomeric formsof the compound (e.g., diastereomers, enantiomers) and mixtures thereof.Structures with a single bold or dashed line, and at least oneadditional simple line, encompass a single enantiomeric series of allpossible diastereomers.

As used herein, the term “about” is meant to account for variations dueto experimental error. All measurements reported herein are understoodto be modified by the term “about,” whether or not the term isexplicitly used, unless explicitly stated otherwise. As used herein, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise.

The term “alkyl” means a straight or branched chain hydrocarbon.Representative examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl and hexyl.Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms,which groups are commonly represented as C₁₋₈ alkyl.

The term “compound”, as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates).

The term “cycloalkyl” means a cyclic, nonaromatic hydrocarbon.Representative examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A cycloalkyl groupcan contain one or more double bonds. Representative examples ofcycloalkyl groups that contain double bonds include cyclopentenyl,cyclohexenyl, cyclohexadienyl and cyclobutadienyl. Common cycloalkylgroups are C₃₋₈ cycloalkyl groups.

The term “excipient”, as used herein, means any pharmaceuticallyacceptable additive, carrier, diluent, adjuvant or other ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration to a patient.Handbook of Pharmaceutical Excipients, 5^(th) Edition, R. C. Rowe, P. J.Sheskey, and S. C. Owen, editors, Pharmaceutical Press, 2005, Hardback,928, 0853696187.

For the terms “for example” and “such as” and grammatical equivalencesthereof, the phrase “and without limitation” is understood to followunless explicitly stated otherwise.

The term “halogen” or “halo” means F, Cl, Br or I.

The term “patient” means subjects including animals, such as dogs, cats,cows, horses, sheep and humans. Particular patients are mammals. Theterm patient includes males and females.

The term “patient in need” means a patient having, or at risk of having,one or more diseases or conditions where the Mcl-1 protein is involved,such as cancers. Identifying a patient in need can be in the judgment ofa subject or a health care professional and can be subjective (e.g.,opinion) or objective (e.g., measurable by a test or diagnostic method).

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrastemal injection, and infusion.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

The term “pharmaceutically acceptable” is employed herein to refer tothose ligands, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for administrationto a patient, commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial. As used herein the language “pharmaceutically acceptablecarrier” includes buffer, sterile water for injection, solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents, and the like, compatible withpharmaceutical administration. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically acceptable carriers include: (1) sugars, suchas lactose, glucose, and sucrose; (2) starches, such as corn starch,potato starch, and substituted or unsubstituted β-cyclodextrin; (3)cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5)malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter andsuppository waxes; (9) oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10)glycols, such as propylene glycol; (11) polyols, such as glycerin,sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyloleate and ethyl laurate; (13) agar; (14) buffering agents, such asmagnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19)ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxiccompatible substances employed in pharmaceutical formulations. Incertain Claims, pharmaceutical compositions provided herein arenon-pyrogenic, i.e., do not induce significant temperature elevationswhen administered to a patient.

The term “pharmaceutically acceptable salt” refers to the relativelynon-toxic, inorganic and organic acid addition salts of a compoundprovided herein. These salts can be prepared in situ during the finalisolation and purification of a compound provided herein, or byseparately reacting the compound in its free base form with a suitableorganic or inorganic acid, and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate,stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, naphthylate, mesylate,glucoheptonate, lactobionate, laurylsulphonate salts, and amino acidsalts, and the like. (See, for example, Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19).

The phrases “systemic administration”, “administered systemically”,“peripheral administration”, and “administered peripherally” as usedherein mean the administration of a ligand, drug, or other material viaroute other than directly into the central nervous system, such that itenters the patient's system and thus, is subject to metabolism and otherlike processes, for example, subcutaneous administration.

The term “therapeutically effective amount” means an amount of acompound that ameliorates, attenuates or eliminates one or more symptomof a particular disease or condition, or prevents or delays the onset ofone of more symptom of a particular disease or condition.

The terms “treating”, “treat” or “treatment” and the like includepreventative (e.g., prophylactic) and palliative treatment.

Embodiments A

The embodiments listed below are presented in numbered form forconvenience and for ease and clarity of reference in referring back tomultiple embodiments.

In a first embodiment, the present invention comprises a compound ofFormula I′:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable salt of the stereoisomer thereof,wherein:

Z is C or N;

Q is O or S;

W is CR^(WA)R^(WB) or C═O;

R^(WA) and R^(WB) are independently selected from H, C₁₋₃alkyl, halo,—OH, or —O—C₁₋₃alkyl;

b, represented by the symbol

is a single or double chemical bond which may be cis or trans;

R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl,—(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), or—C(═O)NR^(a)R^(b);

R² is selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a),—C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or —C(═O)NR^(a)R^(b),

R³ is independently selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or—C(═O)NR^(a)R^(b);

each of R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selected from H, halo,—C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6-to 12-membered arylor heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

alternatively R³ and R⁴ together with the atoms to which they are bondedmay form a 5- to 12-membered ring, optionally containing a heteroatomselected from a N, O or S atom, in addition to the S and N atoms presentin the ring, wherein the ring may optionally contain at least one doublebond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A)substituents;

R^(3A) is independently selected from H, halo, —OH, C₁₋₆haloalkyl,C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—C(═O)NR^(a)R^(b);

each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independentlyselected from H, OH, halo, —C₁₋₆alkyl;

R^(7A) and R^(8A) are absent when b is a double chemical bond;

R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

R^(9A) is independently selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N=N,—C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-memberedheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl,spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A)substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰substituents independently selected from OH, halo, —NR^(c)R^(d),—C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN,—C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-memberedspirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-memberedcycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, ora 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group,wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkylgroups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, Nor S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl,and heterocycloalkyl groups may include a C═O group, and further whereinthe spiroheterocycloalkyl and heterocycloalkyl groups may include a S═Oor SO₂;

alternatively R⁹ and R^(9A) together with Q, W, and the C to which W andQ are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring,optionally containing a heteroatom in addition to Q that is selectedfrom N, O or S, wherein the ring may contain a double bond, wherein thering may optionally include a C═O group, and further wherein the ringoptionally may be substituted by 1, 2, or 3 R¹¹ substituents;

R¹¹ is independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl,—O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c),—OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 6-to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl,and heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independentlyselected from O, N or S, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═Ogroup, and further wherein the spiroheterocycloalkyl andheterocycloalkyl groups may include a S═O or SO₂;

wherein the —C₁₋₆alkyl of any of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R^(4A), R^(5A), R^(6A), R^(7A), R^(8A), and R^(9A)substituents is unsubstituted or substituted by 1, 2 or 3 R¹²substituents independently selected from OH, —OC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, halo, —O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b),—(NR^(a)R^(b)R^(c))_(n), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b),—O—SiR^(a)R^(b)R^(c), —O-(3- to 12-membered heterocycloakyl), phenyl, a6-to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkylor spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl,spirocycloalkyl and spiroheterocycloalkyl groups of any of the R², R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² substituents can be unsubstitutedor substituted with 1, 2, 3 or 4 R¹³ substituents independently selectedfrom OH, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c),—NR^(c)R^(d), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a),—C(═O)OR^(c), —B(OH)₂, a 6-to 12-membered aryl or heteroaryl, a 5- to12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl,and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independentlyselected from O, N or S, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═Ogroup, and further wherein the spiroheterocycloalkyl andheterocycloalkyl groups may include a S═O or SO₂;

wherein each R^(a), R^(b), R^(c), and R^(d) is independently H, OH,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴, NR¹⁴R¹⁴,—SO₂R¹⁴, —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O)R¹⁴, —OC(═O)R¹⁴, —C(═O)OR¹⁴,—C(═O)NR¹⁴R¹⁴, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—C₁₋₆alkyl-OH, benzyl, phenyl, a —C₁₋₆alkyl-3- to 12-memberedheterocycloalkyl, a 6- to 12-membered aryl or heteroaryl, a 5-to12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl,and heterocycloalkyl groups and the heterocycloalkyl group of the—C₁₋₆alkyl-heterocycloalkyl group have 1, 2, 3, or 4 heteroatomsindependently selected from O, N or S, wherein the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, and theheterocycloalkyl groups of the —C₁₋₆alkyl-heterocycloalkyl group mayinclude a C═O group, and further wherein the spiroheterocycloalkyl andheterocycloalkyl groups may include a S═O or SO₂;

the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl,cycloalkyl, heterocycloalkyl and the heterocycloalkyl groups of the—C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) canbe unsubstituted or substituted with 1, 2, 3, or 4 R¹⁴ substituentsindependently selected from H, OH, —N═N=N, halo, —C₁₋₆alkyl,—OC₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, phenyl, tolyl,—C(O)C₁₋₆alkyl, —C(O)OCH₃, SO₂-phenyl, or —SO₂—N(CH₃)₂; and

n is independently, in each instance, an integer of 1, 2, 3 or 4.

2. Another embodiment of the present invention comprises the compound ofEmbodiment 1, wherein the compound of Formula I′ has the Formula I′a:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

3. The compound of any one of Embodiments 1 or 2, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein bis a double bond.

4. The compound of any one of Embodiments 1 or 2, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein bis a single bond.

5. The compound of any one of Embodiments 1-4, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein Zis C.

6. The compound of any one of Embodiments 1-4, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein Zis N.

7. The compound of any one of Embodiments 1-6, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein Qis O.

8. The compound of any one of Embodiments 1-6, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein Qis S.

9. The compound of any one of Embodiments 1-8, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein Wis C═O.

10. The compound of any one of Embodiments 1-8, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein Wis CR^(WA)R^(WB).

11. The compound of any one of Embodiments 1-8 and 10, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(WA) and R^(WB) are both H.

12. The compound of any one of Embodiments 1-11, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹is halo.

13. The compound of any one of Embodiments 1-12, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹is Cl.

14. The compound of any one of Embodiments 1-13, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R²is H.

15. The compound of any one of Embodiments 1-14, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R³is H or —C₁₋₆ alkyl.

16. The compound of any one of Embodiments 1-15, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R³is —CH₃.

17. The compound of any one of Embodiments 1-15, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R³is H.

18. The compound of any one of Embodiments 1-17, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkylhalo,—C₁₋₆alkyl-O—C₁₋₆alkyl, or —(CH₂CH₂O)_(n)R^(a), wherein the —C₁₋₆alkylis unsubstituted or substituted with —OH, (═O), phenyl,—O—SiR^(a)R^(b)R^(c), —NR^(a)R^(b), a 3- to 12-membered cycloalkyl, or a3-to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3,or 4 heteroatoms independently selected from O, N or S.

19. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is H.

20. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is —C₁₋₆alkyl.

21 The compound of any one of Embodiments 1-18 or 20, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is —CH₃.

22. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is —C₁₋₆alkyl-O—C₁₋₆alkyl.

23. The compound of any one of Embodiments 1-18 or 22, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is —CH₂CH₂OCH₃.

24. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is —C₁₋₆alkyl-OH.

25. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is —C₁₋₆alkyl=O.

26. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is —C₁₋₆alkyl-phenyl.

27. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is —C₁₋₆alkyl-O—SiR^(a)R^(b)R^(c).

28. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is —C₁₋₆alkyl-NR^(a)R^(b).

29. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is —C₁₋₆alkyl-C₃-C₆cycloalkyl.

30. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is —C₁₋₆alkyl-C₃-C₁₀heterocycloalkyl having 1, 2, 3, or 4 heteroatomsindependently selected from O, N or S.

31. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is

32. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is

33. The compound of any one of Embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is independently selected from —CH₃, —CH₂CH₂OCH₃,

34. The compound of any one of Embodiments 1-14, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R³and R⁴, together with the atoms to which they are bonded, form a 5- to12-membered ring, optionally containing a heteroatom selected from N, Oor S in addition to the S and N atoms present in the ring, wherein thering may optionally contain at least one double bond; and furtherwherein the ring is substituted with 0, 1, 2, or 3 R^(3A) substituents.

35. The compound of any one of Embodiments 1-14 or 34, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R³ and R⁴ together with the atoms to which they are attachedform

36. The compound of any one of Embodiments 1-35, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵is H or —C₁₋₆ alkyl.

37. The compound of any one of Embodiments 1-36, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵is —CH₃.

38. The compound of any one of Embodiments 1-36, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵is H.

39. The compound of any one of Embodiments 1-38, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶is H or —C₁₋₆ alkyl.

40. The compound of any one of Embodiments 1-38, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶is —CH₃.

41. The compound of any one of Embodiments 1-38, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶is H.

42. The compound of any one of Embodiments 1-41, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereineach of R^(4A), R^(5A), R^(6A), R^(7A) and R^(8A) is independentlyselected from H, OH, halo, or —C₁₋₆alkyl.

43 The compound of Embodiment 42, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein each of R^(4A),R^(5A), R^(6A), R^(7A) and R^(8A) is H.

44. The compound of any one of Embodiments 1, 2, or 4-43, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(7A) and R^(8A) are both H.

45. The compound of any one of Embodiments 1-44, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁷and R⁸ are both H.

46. The compound of any one of Embodiments 1-45, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is independently selected from H, —C₁₋₆alkyl, —C₂₋₆alkenyl, or—C₁₋₆alkyl-O—C₁₋₆alkyl or —C₁₋₆haloalkyl.

47. The compound of any one of Embodiments 1-46, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is H.

48. The compound of any one of Embodiments 1-46, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is —CH₃.

49. The compound of any one of Embodiments 1-46, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is —CH₂CH₃.

50. The compound of any one of Embodiments 1-46, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is —CH₂CH(CH₃)₂.

51. The compound of any one of Embodiments 1-46, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is —CH₂CH₂OCH₃.

52. The compound of any one of Embodiments 1-46, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is —CF₃.

53. The compound of any one of Embodiments 1-52, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl, —C₂₋₆alkenyl—(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N=N, —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-memberedspirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-memberedcycloalkenyl, a 3-to 12-membered monocyclic or bicyclic cycloalkyl, or a3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, whereinthe heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have1, 2, 3, or 4 heteroatoms independently selected from O, N or S, whereinthe cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, andheterocycloalkyl groups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

54. The compound of any one of Embodiments 1-53, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is —C₁₋₆alkyl.

55. The compound of any one of Embodiments 1-53, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is —C(═O)R^(a).

56. The compound of any one of Embodiments 1-53, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is a 3- to 12-membered monocyclic or bicyclic heterocycloalkylgroup, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S.

57. The compound of any one of Embodiments 1-53, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is a 3-to 12-membered monocyclic heterocycloalkyl group, whereinthe heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independentlyselected from O or N.

58. The compound of any one of Embodiments 1-53, 56 or 57, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein the 3- to 12-membered monocyclic heterocycloalkyl R^(9A) groupcan be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituentsindependently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN,—C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-memberedspirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-memberedcycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, ora 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group,wherein the heteroaryl, spiroheterocycloalkyl, or heterocycloalkyl grouphave from 1, 2, 3, or 4 heteroatoms independently selected from O, N orS, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, andheterocycloalkyl groups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

59. The compound of any one of Embodiments 1-58, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinthe 1, 2, 3 or 4 R¹⁰ substituents are independently selected from—C₁₋₆alkyl or a 3- to 12-membered monocyclic heterocycloalkyl group,wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S.

60. The compound of any one of Embodiments 1-59, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR¹⁰ is —C₁₋₆alkyl.

61. The compound of any one of Embodiments 1-59, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group, whereinthe heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independentlyselected from O, N or S.

62. The compound of any one of Embodiments 1-53, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is a 5-to 12-membered bicyclic heterocycloalkyl group, whereinthe heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independentlyselected from O or N.

63. The compound of any one of Embodiments 1-52, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is independently selected from —N═N═N,

64. The compound of any one of Embodiments 1-45, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹and R^(9A) together with Q, W, and the C to which W and Q are bonded,form a 3- to 12-membered monocyclic or bicyclic ring, optionallycontaining a heteroatom in addition to Q selected from N, O or S,wherein the ring may contain a double bond, wherein the ring mayoptionally include a C═O group, and further wherein the ring optionallymay be substituted by 1, 2, or 3 R¹¹ substituents.

65. The compound of any one of Embodiments 1-45 and 64, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ and R^(9A) together with the atoms to which they are bondedform a structure selected from:

66. The compound of any one of Embodiments 1-9, 12-52 or 64, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein when W is C═O, then R^(9A) is

67. The compound of any one of Embodiments 1-11 or 14-66, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R¹ is H.

68. Another embodiment of the present invention comprises the compoundof Embodiment 1, wherein the compound of Formula I′ has Formula II′:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

69. Another embodiment of the present invention comprises the compoundof any one of Embodiments 1, 2, or 68, wherein the compound of FormulaI′ has Formula II′a:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

70. The compound of any one of Embodiments 1, 2, 68, or 69, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkylhalo,—C₁₋₆alkyl-O—C₁₋₆alkyl, or —(CH₂CH₂O)_(n)R^(a), wherein the —C₁₋₆alkylis unsubstituted or substituted with —OH, (═O), phenyl,—O—SiR^(a)R^(b)R^(c), —NR^(a)R^(b), a 3- to 12-membered cycloalkyl, or a3-to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3,or 4 heteroatoms independently selected from O, N or S.

71. The compound of any one of Embodiments 1, 2, 68-69, or 70, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is —CH₃.

72. The compound of any one of Embodiments 1, 2, 68-69, or 70, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is —CH₂CH₂OCH₃.

73. The compound of any one of Embodiments 1, 2, 68-71 or 72, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is H or —C₁₋₆ alkyl.

74. The compound of any one of Embodiments 1, 2, 68-71 or 72, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is —CH₃.

75. The compound of any one of Embodiments 1, 2, 68-71 or 72, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is H.

76. The compound of any one of Embodiments 1, 2, 68-74 or 75, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is H or —C₁₋₆ alkyl.

77. The compound of any one of Embodiments 1, 2, 68-75 or 76, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is —CH₃.

78. The compound of any one of Embodiments 1, 2, 68-75 or 76, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is H.

79. The compound of any one of Embodiments 1, 2, 68-77 or 78 or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3-to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

80. The compound of any one of Embodiments 1, 2, 68-78 or 79, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is —CH₃.

81. The compound of any one of Embodiments 1, 2, 68-78 or 79, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is —CH₂CH₃.

82. The compound of any one of Embodiments 1, 2, 68-80 or 81, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is independently selected from H, C₁₋₆haloalkyl,C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a),—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N=N,—C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-memberedheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

83. The compound of any one of Embodiments 1, 2, 68-81 or 82, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is —C₁₋₆alkyl.

84. The compound of any one of Embodiments 1, 2, 68-81 or 82, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is —C(═O)R^(a).

85. The compound of any one of Embodiments 1, 2, 68-81 or 82, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is a 3-to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3or 4 heteroatoms independently selected from O, N or S.

86. The compound of any one of Embodiments 1, 2, 68-82 or 85, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is a 3-to 12-membered monocyclic heterocycloalkyl group,wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O or N.

87. The compound of any one of Embodiments 1, 2, 68-82 or 85-86, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein the 3- to 12-membered monocyclic heterocycloalkyl R^(9A) groupcan be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituentsindependently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN,—C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-memberedspirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-memberedcycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, ora 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group,wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkylgroups have 1, 2, 3 or 4 heteroatoms independently selected from O, N orS, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, andheterocycloalkyl groups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

88. The compound of any one of Embodiments 1, 2, 68-82 or 85-86, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein the 1, 2, 3 or 4 R¹⁰ substituents are independently selectedfrom —C₁₋₆alkyl or a 3- to 12-membered monocyclic heterocycloalkylgroup, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S.

89. The compound of any one of Embodiments 1, 2, 68-82 or 85-88, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R¹⁰ is —C₁₋₆alkyl.

90. The compound of any one of Embodiments 1, 2, 68-82 or 85-88, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R¹⁰ is a 3-to 12-membered monocyclic heterocycloalkyl group,wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S.

91. The compound of any one of Embodiments 1, 2, 68-82 or 85, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is a 5-to 12-membered bicyclic heterocycloalkyl group,wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O or N.

92. The compound of any one of Embodiments 1, 2, or 68-82, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is independently selected from:

93. Another embodiment of the present invention comprises the compoundof Embodiment 1, wherein the compound of Formula I′ has Formula III′:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof, wherein R⁴, R⁵, R⁹ and R^(9A) are as defined above.

94. Another embodiment of the present invention comprises the compoundof Embodiment 1, 2, or 93, wherein the compound of Formula I′ hasFormula III′a:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

95. The compound of any one of Embodiments 1, 2, or 93-94, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkylhalo,—C₁₋₆alkyl-O—C₁₋₆alkyl, or —(CH₂CH₂O)_(n)R^(a), wherein the —C₁₋₆alkylis unsubstituted or substituted with —OH, —(═O), phenyl,—O—SiR^(a)R^(b)R^(c), —NR^(a)R^(b), a 3- to 12-membered cycloalkyl, or a3- to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2,3, or 4 heteroatoms independently selected from O, N or S.

96. The compound of any one of Embodiments 1, 2, or 93-95, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is —CH₃.

97. The compound of any one of Embodiments 1, 2, or 93-95, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is —CH₂CH₂OCH₃.

98. The compound of any one of Embodiments 1, 2 or 93-97, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is H or —C₁₋₆alkyl.

99. The compound of any one of Embodiments 1, 2 or 93-98, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is —CH₃.

100. The compound of any one of Embodiments 1, 2 or 93-98, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is H.

101. The compound of any one of Embodiments 1, 2 or 93-100, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is H or —C₁₋₆alkyl.

102. The compound of any one of Embodiments 1, 2 or 93-101, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is —CH₃.

103. The compound of any one of Embodiments 1, 2 or 93-101, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is H.

104. The compound of any one of Embodiments 1, 2 or 93-103, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3-to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

105. A compound of any one of Embodiments 1, 2 or 93-104, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is —CH₃.

106. A compound of any one of Embodiments 1, 2 or 93-104, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is —CH₂CH₃.

107. A compound of any one of Embodiments 1, 2 or 93-104, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is —H.

108. A compound of any one of Embodiments 1, 2 or 93-107, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is independently selected from H, C₁₋₆haloalkyl,C₁₋₆alkyl, —C₂₋₆alkenyl —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N=N,—C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-memberedheteroaryl, a 5- to 10-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

109. The compound of any one of Embodiments 1, 2 or 93-108, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is —C₁₋₆alkyl.

110. The compound of any one of Embodiments 1, 2 or 93-108, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is —C(═O)R^(a).

111. The compound of any one of Embodiments 1, 2 or 93-108, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is a 3-to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3or 4 heteroatoms independently selected from O, N or S.

112. The compound of any one of Embodiments 1, 2, 93-108 or 111, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is a 3-to 12-membered monocyclic heterocycloalkyl group,wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O or N.

113. The compound of any one of Embodiments 1, 2, 93-108 or 112, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein the 3- to 12-membered monocyclic heterocycloalkyl R^(9A) groupcan be unsubstituted or substituted with from 1, 2, 3 or 4 R¹⁰substituents independently selected from OH, halo, —NR^(c)R^(d),—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN,—C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-memberedspirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-memberedcycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, ora 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group,wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkylgroups have 1, 2, 3 or 4 heteroatoms independently selected from O, N orS, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, andheterocycloalkyl groups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

114. The compound of any one of Embodiments 1, 2, 93-108 or 112-113, orthe stereoisomer thereof, the pharmaceutically acceptable salt thereof,or the pharmaceutically acceptable salt of the stereoisomer thereof,wherein the 1, 2, 3 or 4 R¹⁰ substituents are independently selectedfrom —C₁₋₆alkyl or a 3- to 12-membered monocyclic heterocycloalkylgroup, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S.

115. The compound of any one of Embodiments 1, 2, 93-108 and 112-114, orthe stereoisomer thereof, the pharmaceutically acceptable salt thereof,or the pharmaceutically acceptable salt of the stereoisomer thereof,wherein R¹⁰ is —C₁₋₆alkyl.

116. The compound of any one of Embodiments 1, 2, 93-108 or 112-113, orthe stereoisomer thereof, the pharmaceutically acceptable salt thereof,or the pharmaceutically acceptable salt of the stereoisomer thereof,wherein R¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group,wherein the heterocycloalkyl group has from 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S.

117. The compound of any one of Embodiments 1, 2, 93-108 or 111, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is a 5-to 12-membered bicyclic heterocycloalkyl group,wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O or N.

118. The compound of any one of Embodiments 1, 2, or 93-108, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is independently selected from:

119. Another embodiment of the present invention comprises the compoundof Embodiment 1, wherein the compound of Formula I′ has Formula IV′:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof, wherein R⁴, R⁵, R⁹ and R^(9A) are as defined above.

120. Another embodiment of the present invention comprises the compoundof Embodiment 1, 2 or 119, wherein the compound of Formula I′ hasFormula IV′a:

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a pharmaceutically acceptable salt of the stereoisomer thereof.

121. The compound of any one of Embodiments 1, 2, or 119-120, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkylhalo,—C₁₋₆alkyl-O—C₁₋₆alkyl, or —(CH₂CH₂O)_(n)R^(a), wherein the —C₁₋₆alkylis unsubstituted or substituted with —OH, —(═O), phenyl,—O—SiR^(a)R^(b)R^(c), —NR^(a)R^(b), a 3- to 12-membered cycloalkyl, or a3- to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2,3, or 4 heteroatoms independently selected from O, N or S.

122. The compound of any one of Embodiments 1, 2, or 119-121, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is —CH₃.

123. The compound of any one of Embodiments 1, 2, or 119-121, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is —CH₂CH₂OCH₃.

124. The compound of any one of Embodiments 1, 2, or 119-123, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is H or —C₁₋₆ alkyl.

125. The compound of any one of Embodiments 1, 2, or 119-124, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is —CH₃.

126. The compound of any one of Embodiments 1, 2, or 119-125, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is H.

127. The compound of any one of Embodiments 1, 2, or 119-126, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is H or —C₁₋₆ alkyl.

128. The compound of any one of Embodiments 1, 2, or 119-127, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is —CH₃.

129. The compound of any one of Embodiments 1, 2, or 119-127, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is H.

130. The compound of any one of Embodiments 1, 2, or 119-129, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl,—C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl orheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

131. The compound of any one of Embodiments 1, 2, or 119-130, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is —CH₃.

132. The compound of any one of Embodiments 1, 2, or 119-130, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁹ is —CH₂CH₃.

133. The compound of any one of Embodiments 1, 2, or 119-132, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is independently selected from H, C₁₋₆haloalkyl,C₁₋₆alkyl, —C₂₋₆alkenyl —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N=N,—C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-memberedheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl group have 1, 2, 3, or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

134. The compound of any one of Embodiments 1, 2, or 119-133, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is —C₁₋₆alkyl.

135. The compound of any one of Embodiments 1, 2, or 119-113, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is —C(═O)R^(a).

136. The compound of any one of Embodiments 1, 2, or 119-133, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is a 3-to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3or 4 heteroatoms independently selected from O, N or S.

137. The compound of any one of Embodiments 1, 2, 119-133 or 136, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is a 3-to 12-membered monocyclic heterocycloalkyl group,wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O or N.

138. The compound of any one of Embodiments 1, 2, 119-133, or 136-137,or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof, wherein the 3- to 12-membered monocyclic heterocycloalkylR^(9A) group can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰substituents independently selected from OH, halo, —NR^(c)R^(d),—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN,—C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-memberedspirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-memberedcycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, ora 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group,wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkylgroups have 1, 2, 3 or 4 heteroatoms independently selected from O, N orS, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, andheterocycloalkyl groups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂.

139. The compound of any one of Embodiments 1, 2, 119-133, or 136-138,or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof, wherein the 1, 2, 3 or 4 R¹⁰ substituents are independentlyselected from —C₁₋₆alkyl or a 3- to 12-membered monocyclicheterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3or 4 heteroatoms independently selected from O, N or S.

140. The compound of any one of Embodiments 1, 2, 119-133, or 136-139,or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof, wherein R¹⁰ is —C₁₋₆alkyl.

141. The compound of any one of Embodiments 1, 2, 119-133, or 136-139,or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof, wherein R¹⁰ is a 3- to 12-membered monocyclic heterocycloalkylgroup, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S.

142. The compound of any one of Embodiments 1, 2, 119-133, or 136, orthe stereoisomer thereof, the pharmaceutically acceptable salt thereof,or the pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is a 5-to 12-membered bicyclic heterocycloalkyl group,wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatomsindependently selected from O or N.

143. The compound of any one of Embodiments 68-70, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is independently selected from:

144. Another embodiment of the present invention comprises the compoundof Embodiment 1, wherein the compound is selected from:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

145. The compound of embodiment 144 or the pharmaceutically acceptablesalt thereof.

146. Another embodiment of the present invention comprises the compoundof Embodiment 1, wherein the compound is selected from:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

147. The compound of embodiment 146 or the pharmaceutically acceptablesalt thereof.

148. Another embodiment of the present invention comprises apharmaceutical composition comprising the compound of any one ofEmbodiments 1-147 or the pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.

149. Another embodiment of the present invention comprises a method oftreating cancer, the method comprising: administering to a patient inneed thereof a therapeutically effective amount of the compound of anyof Embodiments 1-147 or the pharmaceutically acceptable salt thereof.

150. The method of Embodiment 149, wherein the cancer is a hematologicmalignancy.

151. The method of Embodiment 149, wherein the cancer is selected fromthe group consisting of breast cancer, colorectal cancer, skin cancer,melanoma, ovarian cancer, kidney cancer, lung cancer, non-small celllung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiplemyeloma, leukemia, and acute myelogenous leukemia.

152. The method of Embodiment 149, wherein the cancer is multiplemyeloma.

153. The method of Embodiment 149, further comprising administering tothe patient in need thereof a therapeutically effective amount of anadditional pharmaceutically active compound.

154. The method of Embodiment 153, wherein the additionalpharmaceutically active compound is carfilzomib.

155. The method of Embodiment 153, wherein the additionalpharmaceutically active compound is venetoclax.

156. The method of Embodiment 153, wherein the additionalpharmaceutically active compound is cytarabine.

157. Another embodiment of the present invention comprises the use of acompound according to any one of Embodiments 1-147 for treating cancerin a subject.

158. Another embodiment of the present invention comprises the compoundaccording to any one of Embodiments 1-147 in the preparation of amedicament for treating cancer.

159. The compound according to Embodiment 158, wherein the cancer is ahematologic malignancy.

160. The compound according to Embodiment 158, wherein the cancer isselected from the group consisting of breast cancer, colorectal cancer,skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer,non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma,multiple myeloma, leukemia, and acute myelogenous leukemia.

161. The compound according to Embodiment 158, wherein the cancer ismultiple myeloma.

162. The compound according to Embodiment 158, wherein the cancer isacute myelogenous leukemia.

163. The compound according to Embodiment 158, wherein the cancer isnon-Hodgkin's lymphoma.

Embodiments B

The embodiments listed below are presented in numbered form forconvenience and for ease and clarity of reference in referring back tomultiple embodiments.

In a first embodiment, the present invention comprises a compound ofFormula I:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable salt of the stereoisomer thereof,wherein:

Z is C or N;

Q is O, S, CR^(WA)R^(WB), or NR^(a)R^(b);

W is CR^(WA)R^(WB), —C═O, or is absent;

R^(WA) and R^(WB) are independently selected from H, —C₁₋₃alkyl,—C₂₋₃alkenyl, —C₂₋₃alkynyl, halo, —OH, or —O—C₁₋₃alkyl;

b, represented by the symbol

is a single or double chemical bond which may be cis or trans;

R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl,C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a),or —C(═O)NR^(a)R^(b);

R² is selected from H, halo, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkenylene, —C₁₋₆alkyl-O—C₁₋₆alkyl,—(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3-to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl orheterocycloalkyl group have 1, 2, 3 or 4 heteroatoms independentlyselected from O, N or S, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═Ogroup, and further wherein the spiroheterocycloalkyl, andheterocycloalkyl groups may include a S═O or SO₂;

R³ is selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆alkenyl,—(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b);

each of R^(2B), R^(2C), R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selectedfrom H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6-to 12-membered arylor heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl and heterocycloalkyl groups may include a S═O orSO₂;

alternatively R³ and R⁴ together with the atoms to which they are bondedmay form a 5- to 12-membered ring, optionally containing a heteroatomselected from a N, O or S atom, in addition to the S and N atoms presentin the ring, wherein the ring may optionally contain at least one doublebond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A)substituents;

wherein R^(3A) is selected from H, halo, —OH, C₁₋₆haloalkyl, C₁₋₆alkyl,O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a),—SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or—C(═O)NR^(a)R^(b);

each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independentlyselected from H, OH, halo, or —C₁₋₆alkyl;

R^(7A) and R^(8A) are absent when b is a double chemical bond;

alternatively R⁷ and R⁸ together with the atoms to which they are bondedmay form a 3- to 12-membered ring, wherein the ring may optionallycontain at least one double bond;

R⁹ is independently selected from H, OH, —(═O), —C₁₋₆haloalkyl,—C₁₋₆alkyl, —C₁₋₆alkenylene, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, cyano, a 6- to12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl or heterocycloalkyl groups have 1, 2, 3 or 4heteroatoms independently selected from O, N or S, and the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group mayinclude a C═O group, and further wherein the spiroheterocycloalkyl, andheterocycloalkyl groups may include a S═O or SO₂;

R^(9A) is independently selected from H, —OH, halo, cyano,—C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,—C₁₋₆alkenylene, —(CH₂CH₂O)_(n)R^(a), —P(═O)OR^(a)OR^(b), —CSR^(a),—CS(═O)R^(a), —SR^(a), —SOR^(a), —OSO₂R^(a), —SO₂R^(a),—(CH₂CH₂O)_(n)CH₃, —(═O), —C(═O), —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(b), —CH₂—NR^(a)R^(b), —NR^(a)R^(b),—C₁₋₆alkyl-O—C₁₋₆alkyl, —OC₁₋₆alkyl, —O—C₁₋₆alkyl-O—C₁₋₆alkyl, phenyl, a6- to 12-membered aryl, a 6-to 12-membered heteroaryl, a 5- to12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicycliccycloalkyl, or a 3- to 12-membered monocyclic or bicyclicheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyland heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independentlyselected from O, N or S, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, and heterocycloalkyl groups may contain a doublebond and may contain a C═O group, and further wherein thespiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O orSO₂;

wherein R^(9A) is not H when W is absent;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl,spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A)substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰substituents independently selected from OH, halo, —NR^(c)R^(d),—C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN,—C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-memberedspirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-memberedcycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, ora 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group,wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkylgroups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, Nor S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl,and heterocycloalkyl groups may include a C═O group, and further whereinthe spiroheterocycloalkyl and heterocycloalkyl groups may include a S═Oor SO₂;

alternatively R⁷ and R^(9A) together with the atoms to which they arebonded may form a 3- to 12-membered ring, wherein the ring mayoptionally contain at least one double bond;

alternatively R⁹ and R^(9A) together with Q, W, and the C to which W andQ are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring,optionally containing a heteroatom in addition to Q that is selectedfrom N, O or S, wherein the ring may contain a double bond, wherein thering may optionally include a C═O group, and further wherein the ringoptionally may be substituted by 1, 2, or 3 R¹¹ substituents;

R¹¹ is independently selected from H, —OH, halo, —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl,—O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —NR^(c)R^(d), —C(═O)NR^(c)R^(d),—C(═O)R^(c), —OC(═O)R^(c), —C(═O)OR^(c), a 6- to 12-membered aryl orheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3 or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroup may include a double bond, and wherein the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group mayinclude a C═O group, and further wherein the spiroheterocycloalkyl, andheterocycloalkyl groups may include a S═O or SO₂;

wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and the —OC₁₋₆alkyl ofany of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(4A), R^(5A),R^(6A), R^(7A), R^(8A), R^(9A), R^(WA) and R^(WB) substituents isunsubstituted or substituted by 1, 2 or 3 R¹² substituents independentlyselected from OH, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, halo,—O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b), —(NR^(a)R^(b)R^(c))_(n),—OSO₂R^(a), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, —(═O), —C(═O), —C(═O)R^(a),—OC(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —O—SiR^(a)R^(b)R^(c),—SiR^(a)R^(b)R^(c), —O-(3- to 10-membered heterocycloakyl), a 6- to12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O orSO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl,spirocycloalkyl and spiroheterocycloalkyl group of any of the R², R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R^(9A), R¹⁰, R¹¹, R¹², R^(WA) and R^(WB)substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R¹³substituents independently selected from OH, halo, —NR^(c)R^(d),—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl,C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d),—C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl orheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl, and heterocycloalkyl groups of R¹³ have 1, 2, 3or 4 heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl groups of R¹³ orthe heterocycloalkyl group of R¹³ may include a C═O group, and furtherwherein the spiroheterocycloalkyl and heterocycloalkyl groups mayinclude a S═O or SO₂;

wherein each R^(a), R^(b), R^(c), and R^(d) is independently hydrogen,OH, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴,—NR¹⁴R¹⁴, —SO₂R¹⁴, —(CH₂CH₂O)_(n)CH₃, —(═O), —C(═O)R¹⁴, —OC(═O)R¹⁴,—C(═O)OR¹⁴, —C(═O)NR¹⁴R¹⁴, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, benzyl, phenyl, —C₁₋₆alkyl-C(═O)OH,—C₁₋₆alkyl-C(═O)—O—C₁₋₆alkyl, —C₁₋₆alkyl-cycloalkyl,—C₁₋₆alkyl-heterocycloalkyl, —C₁₋₆alkyl-6- to 10-membered aryl,—C₁₋₆alkyl-6- to 10-membered heteroaryl, a 6- to 12-membered aryl orheteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, where the heteroaryl,spiroheterocycloalkyl, heterocycloalkyl group or the—C₁₋₆alkyl-heterocycloalkyl groups have 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S, and the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, group ofR^(a), R^(b), R, and R^(d) or the heterocycloalkyl group or the—C₁₋₆alkyl-heterocycloalkyl group may include a double bond and maycontain a C═O group, and the spiroheterocycloalkyl, or heterocycloalkylmay include a S═O or SO₂;

the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl,cycloalkyl, or heterocycloalkyl group of R^(a), R^(b), R^(c), and R^(d)and the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl groupof R^(a), R^(b), R^(c), and R^(d) can be unsubstituted or substitutedwith 1, 2, 3, or 4 R¹⁴ substituents, wherein each R¹⁴ is independentlyselected from H, —OH, —N═N═N, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl,—OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl,phenyl, tolyl, —C(═O)C₁₋₆alkyl, —C(═O)O—C₁₋₆alkyl, N(CH₃)₂ or—SO₂—N(CH₃)₂; and

wherein n is independently in each instance an integer of 1, 2, 3 or 4.

2. Another embodiment of the present invention comprises the compound ofembodiment 1, wherein the compound has the Formula II:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

3. Another embodiment of the present invention comprises a compound ofany of embodiments 1 or 2, wherein the compound has the Formula IIa:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

4. The compound of any one of embodiments 1-3, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein Qis O, NR^(a)NR^(b), or S.

5. The compound of any one of embodiments 1-4, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein Qis O.

6. The compound of any one of embodiments 1-5, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein Wis CR^(WA)R^(WB), —C═O, or is absent.

7. The compound of embodiment 5, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein W is CR^(WA)R^(WB).

8. The compound of embodiment 5, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein W is absent.

9. The compound of any one of embodiments 1-7, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(WA) and R^(WB) are independently selected from H, (═O), —C₁₋₃alkyl,—C₂₋₃alkenyl, —C₂₋₃alkynyl, halo, —OH, or —O—C₁₋₃alkyl.

10. The compound of embodiment 9, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(WA) and R^(WB)are both H.

11. The compound of embodiment 9, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(WA) is —CH₃.

12. The compound of embodiment 9, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(WB) is —CH₃.

13. The compound of embodiment 9, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(WA) is —OH andR^(WB) is H.

14. The compound of any one of embodiments 1-13, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹is halo.

15. The compound of embodiment 14, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R¹ is C₁.

16. The compound of any one of embodiments 1-15, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R³is selected from H and —C₁₋₆alkyl.

17. The compound of embodiment 16, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R³ is H.

18. The compound of any one of embodiments 1-17, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—C₁₋₆alkyl-OH, —C₁₋₆alkyl-OSO₂CH₃, —C₁₋₆alkyl-phenyl, or —C₁₋₆alkyl-(5-6membered heterocycloalkyl, having one or two heteroatoms independentlyselected from N or O).

19. The compound of any one of embodiments 1-18, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴is independently selected from H, —CH₃, —CH₂CH₃,

20. The compound of embodiment 19, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₃.

21. The compound of any one of embodiments 1-20, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵is selected from H or —C₁₋₆alkyl.

22. The compound of embodiment 21, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁵ is —CH₃.

23. The compound of any one of embodiments 1-22, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶is selected from H or —C₁₋₆alkyl.

24. The compound of embodiment 23, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁶ is H.

25. The compound of any one of embodiments 1-24, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is independently selected from H, —C₁₋₆alkyl, —C₁₋₆haloalkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-(5-6 membered heterocycloalkyl),wherein the heterocycloalkyl has one or two heteroatoms independentlyselected from N or O, or —C₁₋₆alkyl-phenyl, wherein the phenyl of the—C₁₋₆alkyl-phenyl of the R⁹ groups is unsubstituted or substituted with1 or 2 R¹³ substituents selected from halo or —C₁₋₆alkyl-O—C₁₋₆alkyl.

26. The compound of embodiment 25, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁹ is independentlyselected from H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, CH₂CH₂OCH₃, CH₂CF₃,

27. The compound of embodiment 26, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁹ is H.

28. The compound of embodiment 26, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁹ is —C₁₋₆alkyl.

29. The compound of embodiment 26, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₃.

30. The compound of embodiment 26, wherein R⁹ is

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

31. The compound of any one of embodiments 1-24, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinalternatively R⁹ and R^(9A) together with Q, W, and the C to which W andQ are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring,optionally containing a heteroatom in addition to Q that is selectedfrom N, O or S, wherein the ring may contain a double bond, wherein thering may optionally include a C═O group.

32. The compound of embodiment 31, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁹ and R^(9A)together with Q, W and the C to which Q and W are bonded form

33. The compound of any one of embodiments 1-30, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is independently selected from H, OH, —C₁₋₆alkyl, —C₂-C₆ alkenyl,—C₂₋₆alkynyl; —OC₁₋₆alkyl, —CH₂—NR^(a)R^(b), —C(═O)NR^(a)R^(b), —(═O),—C(═O), C(═O)OR^(a), —C(═O)R^(a), cyano, —C₁₋₆haloalkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —O—C₁₋₆alkyl-O—C₁₋₆alkyl, —P(═O)OR^(a)OR^(b),—SR^(a), —OSO₂R^(a), —SOR^(a), —SO₂R^(a), a 6- to 12-membered aryl orheteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a3- to 12-membered unsubstituted monocyclic or bicyclic heterocycloalkylgroup, wherein the aryl, heteroaryl, or heterocycloalkyl group can havefrom 1, 2, 3 or 4 heteroatoms independently selected from O, N or S,wherein the cycloalkyl and the heterocycloalkyl group may contain adouble bond and further wherein the cycloalkyl and the heterocycloalkylgroup may contain a C═O group; wherein the aryl, heteroaryl, cycloalkyl,heterocycloalkyl, group of the R^(9A) substituent can be unsubstitutedor substituted with from 1, 2, 3 or 4 R¹⁰ substituents independentlyselected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₆alkyl, cyano, —C(═O)OR^(c), a 6- to 10-membered aryl,or —SO₂R^(c);

wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and the —OC₁₋₆alkylof any of the R^(9A) and R¹⁰ substituents is unsubstituted orsubstituted by 1, 2 or 3 R¹² substituents independently selected fromOH, halo, —(═O), —OC₁₋₆alkyl, —C₁₋₆alkyl, —NR^(a)R^(b),—SiR^(a)R^(b)R^(c), a 6- to 12-membered aryl or heteroaryl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl,or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independentlyselected from O, N or S, wherein the cycloalkyl or heterocycloalkylgroups may include a C═O group, and further wherein the heterocycloalkylgroup may include a S═O or SO₂;

wherein the —C₁₋₆alkyl groups of the R¹⁰ substituents is unsubstitutedor substituted by 1, 2 or 3 R¹² substituents of —OC₁₋₆alkyl;

wherein the heterocycloalkyl groups of R¹² substituents can beunsubstituted or substituted with from 1, 2, 3 or 4 R¹³ substituentsindependently selected from —NR^(c)R^(d), or —C₁₋₆alkyl;

wherein each R^(a), R^(b), R^(c) and R^(d) is independently hydrogen,OH, —C₁₋₆alkyl, —(CH₂CH₂O)_(n)CH₃, —NR¹⁴R¹⁴, —C₁₋₆alkyl-NR¹⁴R¹⁴, phenyl,—C₁₋₆alkyl-C(═O)OH, —C₁₋₆alkyl-C(═O)—O—C₁₋₆alkyl, —C₁₋₆alkyl-3- to12-membered cycloalkyl, —C₁₋₆alkyl-3- to 12-membered heterocycloalkyl,—C₁₋₆alkyl-6- to 12-membered heteroaryl, a 6- to 12-membered aryl orheteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, whereinthe heteroaryl group, heterocycloalkyl groups of R^(a), R^(b), R^(c),and R^(d) or the heterocycloalkyl group of the—C₁₋₆alkyl-heterocycloalkyl group of R^(a), R^(b), R, and R^(d) has from1, 2, 3, or 4 heteroatoms independently selected from O, N or S, whereinthe cycloalkyl and heterocycloalkyl groups of R^(a), R^(b), R^(c), andR^(d) and the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkylgroups of R^(a), R^(b), R^(c), and R^(d) may include a double bond, andfurther wherein the cycloalkyl and heterocycloalkyl groups of R^(a),R^(b), R^(c), and R^(d) and the heterocycloalkyl group of the—C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) maycontain a C═O group;

the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl groups ofR^(a), R^(b), R^(c), and R^(d) or the heterocycloalkyl groups of the—C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) canbe unsubstituted or substituted with from 1, 2, 3, or 4 R¹⁴substituents, wherein each R¹⁴ is independently selected from H, OH,halo, —C₁₋₆alkyl, N(CH₃)₂, —C₁₋₆haloalkyl, C(═O)CH₃, —C(═O)OCH₃, or—C₁₋₆alkyl-O—C₁₋₆alkyl;

alternatively R^(a) and R^(b) together with the atoms to which they arebonded may form a 4- to 12-membered monocyclic or bicyclic ring,optionally containing a heteroatom selected from N, O or S atom, whichmay contain a double bond; and

wherein n is independently in each instance an integer from 1, 2, 3 or4.

34. The compound of any one of embodiments 1-23, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinR^(9A) is independently selected from H, —CH₃, OH,

35. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is H.

36. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is —CH₃.

37. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is —OH.

38. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

39. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

40. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

41. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

42. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

43. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

44. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

45. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

46. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

47. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

48. The compound of embodiment 34, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

49 Another embodiment of the present invention comprises a compound ofembodiment 1, wherein the compound has the Formula III:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

50. Another embodiment of the present invention comprises a compound ofany one of embodiments 1 or 49, wherein the compound has the FormulaIIIa:

or the stereoisomer thereof, the pharmaceutically acceptable saltthereof, or the pharmaceutically acceptable salt of the stereoisomerthereof.

51. The compound of any one of embodiments 1, or 49-50, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein Q is O, —CR^(a)R^(b), or —NR^(a)R^(b).

52. The compound of embodiment 51, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein Q is O.

53. The compound of embodiment 52, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein Q is —CH₂.

54. The compound of embodiment 52, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein Q is —NR^(a)R^(b).

55. The compound of any one of embodiments 1, or 49-54, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein W is CR^(WA)R^(WB), —C═O, or is absent.

56. The compound of embodiment 55, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein W is CR^(WA)R^(W).

57. The compound of embodiment 55, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein W is absent.

58. The compound of any one of embodiments 1, or 49-56, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(WA) and R^(WB) are independently selected from H, —C₁₋₃alkyl,—C₁₋₃alkenyl, —C₁₋₃alkynyl, halo, —OH, or —O—C₁₋₃alkyl.

59. The compound of embodiment 58, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(WA) and R^(WB)are both H.

60. The compound of embodiment 58, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(WA) is —CH₃.

61. The compound of embodiment 58, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein at least one ofR^(WA) and R^(WB) is H.

62. The compound of embodiment 58, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(WA) is —OH andR^(WB) is H.

63. The compound of any one of embodiments 1, or 49-62, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R¹ is halo.

64. The compound of embodiment 63, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R¹ is Cl.

65. The compound of any one of embodiments 1, or 49-64, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R³ is H.

66. The compound of any one of embodiments 1, or 49-65, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁴ is independently selected from H or —C₁₋₆alkyl.

67. The compound of embodiment 66, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₃.

68. The compound of any one of embodiments 1, or 49-67, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁵ is selected from H or —C₁₋₆alkyl.

69. The compound of embodiment 68, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁵ is —CH₃.

70. The compound of any one of embodiments 1, or 49-69, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁶ is H.

71. The compound of any one of embodiments 1, or 49-70, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁷ is selected from H or —NR^(a)R^(b).

72. The compound of embodiment 71, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁷ is H.

73. The compound of any one of embodiments 1, or 49-73, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R⁸ is selected from H or —C₁₋₆alkyl.

74. The compound of embodiment 73, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁸ is H.

75. The compound of any one of embodiments 1, or 49-70, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein alternatively R⁷ and R⁸ together with the atoms to which theyare bonded may form a 3- to 12-membered ring.

76. The compound of any one of embodiments 1, 49-70, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, whereinalternatively R⁷ and R^(9A) together with the atoms to which they arebonded may form a 3- to 12-membered ring, wherein the ring mayoptionally contain at least one double bond.

77. The compound of any one of embodiments 1, 49-76, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is independently selected from H, —OH, —(═O), —C₁₋₆alkyl, cyano,—C(═O)—C₁₋₆alkyl, —C(═O)-phenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—C₁₋₆alkyl-(5-10 membered mono or bicyclic heterocycloalkyl), whereinthe heterocycloalkyl may contain one, two, three or four heteroatomsindependently selected from N or O.

78. The compound of any one of embodiments 1, or 49-75, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein alternatively R⁹ and R^(9A) together with Q, W and the C towhich Q and W are bonded, may form a 3- to 12-membered monocyclic orbicyclic ring, optionally containing a heteroatom in addition to Qselected from N, O or S atom, the ring may contain a double bond, thering may optionally include a C═O group, and the ring optionally may besubstituted with 0, 1, 2, or 3 R¹¹ substituents;

wherein R¹¹ is selected from H, halo, —OH, —C₁₋₆haloalkyl, —C₁₋₆alkyl,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —C(═O)R^(c), —C(═O)NR^(c)R^(d), —NR^(c)R^(d),a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherethe heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independentlyselected from O, N or S, wherein the heterocycloalkyl groups may includea double bond, and wherein the heterocycloalkyl groups may contain a C═Ogroup; and further wherein the heterocycloalkyl groups may beunsubstituted or substituted with one or more —C₁₋₆alkyl.

79. The compound of any one of embodiments 1, 49-75 or 77, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is independently selected from H, —OH, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆ alkynyl, —C₁₋₆alkyl, —C(═O), —(═O), —C(═O)R^(a), cyano,—C₁₋₆alkyl-O—C₁₋₆alkyl, —O—C₁₋₆alkyl-O—C₁₋₆alkyl, —OR^(a), —CSRa,—CS(═O)R^(a), —SOR^(a), —NR^(a)R^(b), —C(═O)NR^(a)R^(b), phenyl, a 6- to12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl orspiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-memberedmonocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryland heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independentlyselected from O, N or S, and the cycloalkyl and heterocycloalkyl groupsmay contain a double bond and wherein the cycloalkyl andheterocycloalkyl groups may contain a C═O group, and further wherein theheterocycloalkyl groups may include a S═O or SO₂;

wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups ofthe R^(9A) substituent can be unsubstituted or substituted with from 1,2, 3 or 4 R¹⁰ substituents independently selected from halo,—NR^(c)R^(d), or —C₁₋₆alkyl;

wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and the —OC₁₋₆alkylof any of the R^(9A) and R¹⁰ substituents is unsubstituted orsubstituted by 1, 2 or 3 R¹² substituents independently selected fromOH, halo, —(═O), —OC₁₋₆alkyl, —C₁₋₆alkyl, —NR^(a)R^(b),—SiR^(a)R^(b)R^(c), a 6- to 12-membered aryl or heteroaryl, or a 3- to12-membered monocyclic or bicyclic heterocycloalkyl group, where theheteroaryl or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatomsindependently selected from O, N or S, and the heterocycloalkyl groupsmay include a C═O group.

80. The compound of any one of embodiments 1, 49-76, or the stereoisomerthereof, the pharmaceutically acceptable salt thereof, or thepharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹is independently selected from H, —OH, —CH₃, —CH₂CH₃, —C(═O)CH₃,—CH₂C(═O)OCH₂CH₃, or

81. The compound of embodiment 80, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁹ is H.

82. The compound of embodiment 80, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₃.

83. The compound of any one of embodiments 1, 49-75, or 77-80, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein R^(9A) is independently selected from H, —OH, —CH₃, —CH₂CH₃,—OCH₂C(═O)OCH₂CH₃,

84. The compound of embodiment 83, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is H.

85. The compound of embodiment 83, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is—C₁₋₆alkyl.

86. The compound of embodiment 83, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is —CH₃.

87. The compound of embodiment 83, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R^(9A) is

88. The compound of any one of embodiments 1, 49-75 and 78, or thestereoisomer thereof, the pharmaceutically acceptable salt thereof, orthe pharmaceutically acceptable salt of the stereoisomer thereof,wherein alternatively R⁹ and R^(9A) together with the atoms to whichthey are bonded may form a 5- to 12-membered monocyclic or bicyclicring, optionally containing a heteroatom in addition to Q selected fromN, O or S atom, further wherein the 5-12 membered ring may contain adouble bond.

89. The compound of embodiment 88, or the stereoisomer thereof, thepharmaceutically acceptable salt thereof, or the pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein R⁹ and R^(9A)together with Q, W and the C to which Q and W are bonded form

90. Another embodiment of the present invention comprises a compound,wherein the compound has a structure selected from:

or a stereoisomer thereof; a pharmaceutically acceptable salt thereof, apharmaceutically acceptable salt of the stereoisomer thereof.

91. Another embodiment of the present invention comprises a compound,wherein the compound has a structure selected from:

or a stereoisomer thereof; a pharmaceutically acceptable salt thereof, apharmaceutically acceptable salt of the stereoisomer thereof.

92. The compound of embodiment 91 or the pharmaceutically acceptablesalt thereof.

93. Another embodiment of the present invention comprises apharmaceutical composition comprising the compound of any one ofembodiments 1-92 or the pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.

94. Another embodiment of the present invention comprises a method oftreating cancer, the method comprising: administering to a patient inneed thereof a therapeutically effective amount of the compound of anyof embodiments 1-92 or a pharmaceutically acceptable salt thereof.

95. The method of embodiment 94, wherein the cancer is a hematologicmalignancy.

96. The method of embodiment 94, wherein the cancer is selected from thegroup consisting of breast cancer, colorectal cancer, skin cancer,melanoma, ovarian cancer, kidney cancer, lung cancer, non-small celllung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiplemyeloma, leukemia, and acute myelogenous leukemia.

97. The method of embodiment 94, wherein the cancer is multiple myeloma.

98. The method of embodiment 94, further comprising administering to thepatient in need thereof a therapeutically effective amount of anadditional pharmaceutically active compound.

99. The method of embodiment 98, wherein the additional pharmaceuticallyactive compound is carfilzomib.

100. The method of embodiment 98, wherein the additionalpharmaceutically active compound is venetoclax.

101. The method of embodiment 98, wherein the additionalpharmaceutically active compound is cytarabine.

102. Another embodiment of the present invention comprises a use of acompound according to any one of Embodiments 1-92 for treating cancer ina subject.

103. Another embodiment of the present invention comprises a compoundaccording to any one of Embodiments 1-92 in the preparation of amedicament for treating cancer.

104. The compound according to Embodiment 103, wherein the cancer is ahematologic malignancy.

105. The compound according to embodiment 102, wherein the cancer isselected from the group consisting of breast cancer, colorectal cancer,skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer,non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma,multiple myeloma, leukemia, and acute myelogenous leukemia.

106. The compound according to Embodiment 102, wherein the cancer ismultiple myeloma.

107. The compound according to Embodiment 102, wherein the cancer isacute myelogenous leukemia.

108. The compound according to Embodiment 102, wherein the cancer isnon-Hodgkin's lymphoma.

Another embodiment of the present invention is directed to a method ofinhibiting myeloid cell leukemia 1 protein (Mcl-1) of a cell comprisingcontacting the cell with the compound of Formula I in an effectiveamount to inhibit the Mcl-1, in conjunction with any of the above orbelow embodiments. In one embodiment, the contacting is in vitro. Inanother embodiment, the contacting is in vivo. In one embodiment, thecontacting comprises administering the compound to a subject. In oneembodiment, the administering is oral, parenteral, via injection, viainhalation, transdermal, or transmucosal. In one embodiment, the subjectsuffers from cancer.

One embodiment of the present invention is directed to a method of thetreatment of cancer, comprising administering to a patient in needthereof a therapeutically effective amount of the compound of Formula Ior a pharmaceutical composition comprising the compound of Formula I, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, in conjunction with any of the above or belowembodiments. In one embodiment, the cancer is a hematologic malignancy.In one embodiment, the cancer is selected from the group consisting ofbreast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer,kidney cancer, lung cancer, non-small cell lung cancer, lymphoma,non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acutemyelogenous leukemia. In one embodiment, the cancer is multiple myeloma.In another embodiment, the method further comprises the step ofadministering to the patient in need thereof a therapeutically effectiveamount of at least one additional pharmaceutically active compound. Inone embodiment, the additional pharmaceutically active compound iscarfilzomib, in conjunction with any of the above embodiments.

The methods provided herein include the manufacture and use ofpharmaceutical compositions, which include one or more of the compoundsprovided herein. Also included are the pharmaceutical compositionsthemselves.

In some Claims, a compound provided herein may contain one or moreacidic functional groups and, thus, is capable of formingpharmaceutically acceptable salts with pharmaceutically acceptablebases. The term “pharmaceutically acceptable salts” in these instancesrefers to the relatively non-toxic inorganic and organic base additionsalts of a compound provided herein. These salts can likewise beprepared in situ during the final isolation and purification of thecompound, or by separately reacting the purified compound in its freeacid form with a suitable base, such as the hydroxide, carbonate, orbicarbonate of a pharmaceutically acceptable metal cation, with ammonia,or with a pharmaceutically acceptable organic primary, secondary, ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, and aluminum salts,and the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, and the like (see, forexample, Berge et al., supra).

Wetting agents, emulsifiers, and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring, and perfuming agents,preservatives and antioxidant.

Examples of pharmaceutically acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like;(2) oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

A pharmaceutical composition may also contain adjuvants such aspreservatives, wetting agents, emulsifying agents, and dispersingagents. Prevention of the action of microorganisms may be ensured by theinclusion of various antibacterial and antifungal agents, for example,paraben, chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include tonicity-adjusting agents, such as sugars and thelike into the compositions. In addition, prolonged absorption of theinjectable pharmaceutical form may be brought about by the inclusion ofagents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of one or more compoundsprovided herein, it is desirable to slow the absorption of the compoundfrom subcutaneous or intramuscular injection. For example, delayedabsorption of a parenterally administered compound can be accomplishedby dissolving or suspending the compound in an oil vehicle.

The compounds of the present invention are administered to a patient ina therapeutically effective amount. The compounds can be administeredalone or as part of a pharmaceutically acceptable composition orformulation. In addition, the compounds or compositions can beadministered all at once, as for example, by a bolus injection, multipletimes, such as by a series of tablets, or delivered substantiallyuniformly over a period of time, as for example, using transdermaldelivery. The dose of the compound or composition can be varied overtime. All combinations, delivery methods and administration sequencesare contemplated.

The compounds of the present invention and in some Claims, otheradditional pharmaceutically active compounds, can be administered to apatient either orally, rectally, parenterally, (for example,intravenously, intramuscularly, or subcutaneously) intracistemally,intravaginally, intraperitoneally, intravesically, locally (for example,powders, ointments or drops), or as a buccal or nasal spray. All methodsthat are used by those skilled in the art to administer apharmaceutically active agent are contemplated.

Compositions prepared as described herein can be administered in variousforms, depending on the disorder to be treated and the age, condition,and body weight of the patient, as is well known in the art. Forexample, where the compositions are to be administered orally, they maybe formulated as tablets, capsules, granules, powders, or syrups; or forparenteral administration, they may be formulated as injections(intravenous, intramuscular, or subcutaneous), drop infusionpreparations, or suppositories. For application by the ophthalmic mucousmembrane route, they may be formulated as eye drops or eye ointments.These formulations can be prepared by conventional means in conjunctionwith the methods described herein, and, if desired, the activeingredient may be mixed with any conventional additive or excipient,such as a binder, a disintegrating agent, a lubricant, a corrigent, asolubilizing agent, a suspension aid, an emulsifying agent, or a coatingagent.

Formulations suitable for oral administration may be in the form ofcapsules (e.g., gelatin capsules), cachets, pills, tablets, lozenges(using a flavored basis, usually sucrose and acacia or tragacanth),powders, troches, granules, or as a solution or a suspension in anaqueous or non-aqueous liquid, or as an oil-in-water or water-in-oilliquid emulsion, or as an elixir or syrup, or as pastilles (using aninert matrix, such as gelatin and glycerin, or sucrose and acacia)and/or as mouthwashes, and the like, each containing a predeterminedamount of a compound provided herein as an active ingredient. Acomposition may also be administered as a bolus, electuary, or paste.Oral compositions generally include an inert diluent or an ediblecarrier.

Pharmaceutically compatible binding agents, and/or adjuvant materialscan be included as part of an oral composition. In solid dosage formsfor oral administration (capsules, tablets, pills, dragees, powders,granules, and the like), the active ingredient can be mixed with one ormore pharmaceutically acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, cyclodextrins, lactose, sucrose, saccharin,glucose, mannitol, and/or silicic acid; (2) binders, such as, forexample, carboxymethylcellulose, microcrystalline cellulose, gumtragacanth, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/oracacia; (3) humectants, such as glycerol; (4) disintegrating agents,such as agar-agar, calcium carbonate, potato, corn, or tapioca starch,alginic acid, Primogel, certain silicates, and sodium carbonate; (5)solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, acetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, Sterotes, solid polyethyleneglycols, sodium lauryl sulfate, and mixtures thereof, (10) a glidant,such as colloidal silicon dioxide; (11) coloring agents; and (12) aflavoring agent such as peppermint, methyl salicylate, or orangeflavoring. In the case of capsules, tablets, and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugars, as well as high molecular weight polyethylene glycols, andthe like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of a powdered compound moistenedwith an inert liquid diluent.

Tablets, and other solid dosage forms, such as dragees, capsules, pills,and granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes, microspheres, and/or nanoparticles. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved in sterile water, or some othersterile injectable medium immediately before use. These compositions mayalso optionally contain opacifying agents and may be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding compositions which can be used includepolymeric substances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups,and elixirs. In addition to the active ingredient, the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents, and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, germ, olive,castor, and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols, and fatty acid esters of sorbitan, and mixturesthereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compound(s) may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Pharmaceutical compositions suitable for parenteral administration caninclude one or more compounds provided herein in combination with one ormore pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

In one Claim, the IV formulation consists of a composition containinghydroxypropyl beta cyclodextrin within a pH range between 8-10 as abuffered or unbuffered solution. The IV formulation can be formulated asa sterile solution ready for injection, a sterile solution ready fordilution into an IV admixture or a sterile solid for reconstitution. TheAPI in the IV formulation may exist as a free acid/base or an in situsalt.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions provided herein includewater for injection (e.g., sterile water for injection), bacteriostaticwater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol such as liquid polyethylene glycol, and the like),sterile buffer (such as citrate buffer), and suitable mixtures thereof,vegetable oils, such as olive oil, injectable organic esters, such asethyl oleate, and Cremophor EL™ (BASF, Parsippany, N.J.). In all cases,the composition must be sterile and should be fluid to the extent thateasy syringability exists. Proper fluidity can be maintained, forexample, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

The composition should be stable under the conditions of manufacture andstorage and must be preserved against the contaminating action ofmicroorganisms such as bacteria and fungi. Prevention of the action ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, ascorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, polyalcohols such asmannitol, sorbitol, and sodium chloride in the composition. Prolongedabsorption of the injectable compositions can be brought about byincluding in the composition an agent that delays absorption, forexample, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle, which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the methods of preparation arefreeze-drying (lyophilization), which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Injectable depot forms can be made by forming microencapsule ornanoencapsule matrices of a compound provided herein in biodegradablepolymers such as polylactide-polyglycolide. Depending on the ratio ofdrug to polymer, and the nature of the particular polymer employed, therate of drug release can be controlled. Examples of other biodegradablepolymers include poly(orthoesters) and poly(anhydrides). Depotinjectable formulations are also prepared by entrapping the drug inliposomes, microemulsions or nanoemulsions, which are compatible withbody tissue.

For administration by inhalation, the compounds can be delivered in theform of an aerosol spray from a pressured container or dispenser thatcontains a suitable propellant (e.g., a gas such as carbon dioxide) or anebulizer. Such methods include those described in U.S. Pat. No.6,468,798. Additionally, intranasal delivery can be accomplished, asdescribed in, inter alia, Hamajima et al., Clin. Immunol. Immunopathol.,88(2), 205-10 (1998). Liposomes (e.g., as described in U.S. Pat. No.6,472,375, which is incorporated herein by reference in its entirety),microencapsulation and nanoencapsulation can also be used. Biodegradabletargetable microparticle delivery systems or biodegradable targetablenanoparticle delivery systems can also be used (e.g., as described inU.S. Pat. No. 6,471,996, which is incorporated herein by reference inits entirety).

Systemic administration of a therapeutic compound as described hereincan also be by transmucosal or transdermal means. Dosage forms for thetopical or transdermal administration of a compound provided hereininclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches, and inhalants. The active component may be mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants which may be required.For transmucosal or transdermal administration, penetrants appropriateto the barrier to be permeated are used in the formulation. Suchpenetrants are generally known in the art, and include, for example, fortransmucosal administration, detergents, bile salts, and fusidic acidderivatives. Transmucosal administration can be accomplished through theuse of nasal sprays or suppositories. For transdermal administration,the active compounds are formulated into ointments, salves, gels, orcreams as generally known in the art.

The ointments, pastes, creams, and gels may contain, in addition to oneor more compounds provided herein, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc, and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound providedherein, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates, and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

A compound provided herein can be administered by aerosol. This isaccomplished by preparing an aqueous aerosol, liposomal preparation, orsolid particles containing a compound or composition provided herein. Anonaqueous (e.g., fluorocarbon propellant) suspension could be used. Insome Claims, sonic nebulizers are used because they minimize exposingthe agent to shear, which can result in degradation of the compound.

Ordinarily, an aqueous aerosol can be made by formulating an aqueoussolution or suspension of the agent together with conventionalpharmaceutically acceptable carriers and stabilizers. The carriers andstabilizers vary with the requirements of the particular composition,but typically include nonionic surfactants (TWEEN® (polysorbates),PLURONIC® (poloxamers), sorbitan esters, lecithin, CREMOPHOR®(polyethoxylates)), pharmaceutically acceptable co-solvents such aspolyethylene glycol, innocuous proteins like serum albumin, sorbitanesters, oleic acid, lecithin, amino acids such as glycine, buffers,salts, sugars, or sugar alcohols. Aerosols generally are prepared fromisotonic solutions.

Transdermal patches have the added advantage of providing controlleddelivery of a compound provided herein to the body. Such dosage formscan be made by dissolving or dispersing the agent in the proper medium.Absorption enhancers can also be used to increase the flux of thecompound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

The pharmaceutical compositions can also be prepared in the form ofsuppositories or retention enemas for rectal and/or vaginal delivery.Formulations presented as a suppository can be prepared by mixing one ormore compounds provided herein with one or more suitable nonirritatingexcipients or carriers comprising, for example, cocoa butter,glycerides, polyethylene glycol, a suppository wax or a salicylate,which is solid at room temperature, but liquid at body temperature and,therefore, will melt in the rectum or vaginal cavity and release theactive agent. Formulations which are suitable for vaginal administrationalso include pessaries, tampons, creams, gels, pastes, foams, or sprayformulations containing such carriers as are known in the art to beappropriate.

In one claim, the therapeutic compounds are prepared with carriers thatwill protect the therapeutic compounds against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Suchformulations can be prepared using standard techniques, or obtainedcommercially (e.g., from Alza Corporation and Nova Pharmaceuticals,Inc). Liposomal suspensions (including liposomes targeted to selectedcells with monoclonal antibodies to cellular antigens) can also be usedas pharmaceutically acceptable carriers. These can be prepared accordingto methods known to those skilled in the art, for example, as describedin U.S. Pat. No. 4,522,811, which is incorporated herein by reference inits entirety for all purposes.

The compounds of the present invention are used in the treatment ofdiseases, disorders or symptoms mediated by Mcl-1 inhibition. Examplesof diseases, disorders or symptoms mediated by Mcl-1 inhibition include,but are not limited to, cancers. Non-limiting examples of cancersinclude breast cancer, colorectal cancer, skin cancer, melanoma, ovariancancer, kidney cancer, lung cancer, non-small cell lung cancer,lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia,and acute myelogenous leukemia.

The cancers can include carcinomas (originating in the outer layer ofcells of the skin and internal membranes, e.g., breasts, kidneys, lungs,skin); sarcomas (arising from connective tissue such as bone, muscle,cartilage, and blood vessels), and hematologic malignancies (e.g.,lymphomas and leukemias, which arise in the blood or blood-formingorgans such as the spleen, lymph nodes, and bone marrow). Cancer cellscan include, for example, tumor cells, neoplastic cells, malignantcells, metastatic cells, and hyperplastic cells.

In an Claim, the disease, disorder or symptom is a hyperproliferativedisorder, e.g., a lymphoma, leukemia, carcinoma (e.g., renal, breast,lung, skin), multiple myeloma, or a sarcoma. In one Claim, the leukemiais acute myeloid leukemia. In one Claim, the hyperproliferative disorderis a relapsed or refractory cancer.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions provided herein may be varied so as to obtain an amount ofthe active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The specific dosage and dosage range depends on a number of factors,including the requirements of the patient, the severity of the conditionor disease being treated, the pharmacokinetic characteristics of thecompound(s) employed, and the route of administration. In some Claims,the compositions provided herein can be provided in an aqueous solutioncontaining about 0.1-10% w/v of a compound disclosed herein, among othersubstances, for parenteral administration. Typical dose ranges caninclude from about 0.01 to about 50 mg/kg of body weight per day, givenin 1-4 divided doses. Each divided dose may contain the same ordifferent compounds. The dosage will be a therapeutically effectiveamount depending on several factors including the overall health of apatient, and the formulation and route of administration of the selectedcompound(s).

Dosage forms or compositions containing a compound as described hereinin the range of 0.005% to 100% with the balance made up from non-toxiccarrier may be prepared. Methods for preparation of these compositionsare known to those skilled in the art. The contemplated compositions maycontain about 0.001%-100% active ingredient, in one Claim from about 0.1to about 95%, in another Claim from about 75 to about 85%. Although thedosage will vary depending on the symptoms, age and body weight of thepatient, the nature and severity of the disorder to be treated orprevented, the route of administration and the form of the drug, ingeneral, a daily dosage of from about 0.01 to about 3,000 mg of thecompound is recommended for an adult human patient, and this may beadministered in a single dose or in divided doses. The amount of activeingredient which can be combined with a carrier material to produce asingle dosage form will generally be that amount of the compound whichproduces a therapeutic effect.

The pharmaceutical composition may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the disease being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular patient, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe Claimed compositions.

The precise time of administration and/or amount of the composition thatwill yield the most effective results in terms of efficacy of treatmentin a given patient will depend upon the activity, pharmacokinetics, andbioavailability of a particular compound, physiological condition of thepatient (including age, sex, disease type and stage, general physicalcondition, responsiveness to a given dosage, and type of medication),route of administration, etc. However, the above guidelines can be usedas the basis for fine-tuning the treatment, e.g., determining theoptimum time and/or amount of administration, which will require no morethan routine experimentation consisting of monitoring the patient andadjusting the dosage and/or timing.

The compounds of the present invention can be administered alone, incombination with other compounds of the present invention, or with otherpharmaceutically active compounds or agents. The other pharmaceuticallyactive compounds/agents can be intended to treat the same disease orcondition as the compounds of the present invention or a differentdisease or condition. If the patient is to receive or is receivingmultiple pharmaceutically active compounds or agents, the compounds canbe administered simultaneously, or sequentially.

The compounds of the present invention, or pharmaceutically acceptablesalts thereof, may be used in combination with one or more additionalpharmaceutically active compounds/agents.

One or more additional pharmaceutically active compounds or agents maybe administered separately, as part of a multiple dose regimen, from thecompound of Formula I (e.g., sequentially, e.g., on differentoverlapping schedules with the administration of one or more compoundsof Formula I (including any subgenera or specific compounds thereof). Inother Claims, the one or more additional compounds/agents may be part ofa single dosage form, mixed together with the compound of Formula I in asingle composition. In still another Claim, the one or more additionalcompounds/agents can be given as a separate dose that is administered atabout the same time that one or more compounds of Formula I areadministered (e.g., simultaneously with the administration of one ormore compounds of Formula I (including any subgenera or specificcompounds thereof). Both the compound of Formula I and the one or moreadditional compounds/agents can be present at dosage levels of betweenabout 1 to 100%, and more preferably between about 5 to 95% of thedosage normally administered in a monotherapy regimen.

In a particular claim, the additional pharmaceutically activecompound/agent is a compound or agent that can be used to treat acancer. For example, the additional pharmaceutically activecompound/agent can be selected from antineoplastic agents,anti-angiogenic agents, chemotherapeutic agents, and peptidal cancertherapy agents. In another Claim, the antineoplastic agents are selectedfrom antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents, kinaseinhibitors, proteasome inhibitors, and combinations thereof. It is notedthat the additional pharmaceutically active compound/agent may be atraditional small organic chemical molecule or can be a macromoleculesuch as a protein, antibody, peptibody, DNA, RNA or a fragment of suchmacromolecules.

Examples of additional pharmaceutically active compounds/agents that canbe used in the treatment of cancers and that can be used in combinationwith one or more compounds of the present invention include: acemannan;aclarubicin; aldesleukin; alitretinoin; amifostine; amrubicin;amsacrine; anagrelide; arglabin; arsenic trioxide; BAM 002 (Novelos);bicalutamide; broxuridine; celmoleukin; cetrorelix; cladribine;clotrimazole; cytarabine; DA 3030 (Dong-A); daclizumab; denileukindiftitox; deslorelin; dilazep; docosanol; doxercalciferol;doxifluridine; bromocriptine; cytarabine; HIT diclofenac; interferonalfa; tretinoin; edelfosine; edrecolomab; eflomithine; emitefur;epirubicin; epoetin beta; etoposide phosphate; exisulind; fadrozole;finasteride; fludarabine phosphate; formestane; fotemustine; galliumnitrate; gemtuzumab zogamicin; gimeracil/oteracil/tegafur combination;glycopine; goserelin; heptaplatin; human chorionic gonadotropin; humanfetal alpha fetoprotein; ibandronic acid; interferon alfa; interferonalfa natural; interferon alfa-2; interferon alfa-2a; interferon alfa-2b;interferon alfa-N1; interferon alfa-n3; interferon alfacon-1; interferonalpha natural; interferon beta; interferon beta-1a; interferon beta-1b;interferon gamma natural; interferon gamma-1a; interferon gamma-1b;interleukin-1 beta; iobenguane; irsogladine; lanreotide; LC 9018(Yakult); leflunomide; lenograstim; lentinan sulfate; letrozole;leukocyte alpha interferon; leuprorelin; levamisole+fluorouracil;liarozole; lobaplatin; lonidamine; lovastatin; masoprocol; melarsoprol;metoclopramide; mifepristone; miltefosine; mirimostim; mismatched doublestranded RNA; mitoguazone; mitolactol; mitoxantrone; molgramostim;nafarelin; naloxone+pentazocine; nartograstim; nedaplatin; nilutamide;noscapine; novel erythropoiesis stimulating protein; NSC 631570octreotide; oprelvekin; osaterone; paclitaxel; pamidronic acid;peginterferon alfa-2b; 243rimethyl polysulfate sodium; pentostatin;picibanil; pirarubicin; rabbit antithymocyte polyclonal antibody;polyethylene glycol interferon alfa-2a; porfimer sodium; raltitrexed;rasburicase; rhenium Re 186 etidronate; RII retinamide; romurtide;samarium (153 Sm) lexidronam; sargramostim; sizofuran; sobuzoxane;sonermin; strontium-89 chloride; suramin; tasonermin; tazarotene;tegafur; temoporfin; teniposide; tetrachlorodecaoxide; thymalfasin;thyrotropin alfa; toremifene; tositumomab-iodine 131; treosulfan;tretinoin; trilostane; trimetrexate; triptorelin; trametinib; tumornecrosis factor alpha natural; ubenimex; bladder cancer vaccine;Maruyama vaccine; melanoma lysate vaccine; valrubicin; venetoclax;verteporfin; virulizin; zinostatin stimalamer; abarelix; AE 941(Aeterna); ambamustine; antisense oligonucleotide; bcl-2 (Genta); APC8015 (Dendreon); dexaminoglutethimide; diaziquone; EL 532 (Elan); EM 800(Endorecherche); eniluracil; etanidazole; fenretinide; galocitabine;gastrin 17 immunogen; HLA-B7 gene therapy (Vical); granulocytemacrophage colony stimulating factor; histamine dihydrochloride;ibritumomab tiuxetan; ilomastat; IM 862 (Cytran); interleukin-2;iproxifene; LDI 200 (Milkhaus); leridistim; lintuzumab; CA 125monoclonal antibody (Mab) (Biomira); cancer Mab (Japan PharmaceuticalDevelopment); HER-2 and Fc Mab (Medarex); idiotypic 105AD7 Mab (CRCTechnology); idiotypic CEA Mab (Trilex); LYM-1-iodine 131 Mab(Techniclone); polymorphic epithelial mucin-yttrium 90 Mab (Antisoma);marimastat; menogaril; mitumomab; motexafin gadolinium; MX 6 (Galderma);nolatrexed; P 30 protein; pegvisomant; porfiromycin; prinomastat; RL0903 (Shire); rubitecan; satraplatin; sodium phenylacetate; sparfosicacid; SRL 172 (SR Pharma); SU 5416 (SUGEN); TA 077 (Tanabe);tetrathiomolybdate; thaliblastine; thrombopoietin; tin ethyletiopurpurin; tirapazamine; cancer vaccine (Biomira); melanoma vaccine;melanoma oncolysate vaccine; viral melanoma cell lysates vaccine;valspodarl; fluorouracil; 5-fluorouracil; 244rimethyla; imatinib;altretamine; cladibrine; cyclophosphamine; decarazine; irinotecan;mitosmycin; mitoxane; topotecan; vinorelbine; 244rimethyla; mithram;imiquimod; alemtuzmab; exemestane; bevacizumab; cetuximab; azacitidine;clofarabine; decitabine; desatinib; dexrazoxane; docetaxel; epirubicin;oxaliplatin; erlotinib; raloxifene; fulvestrant; letrozole; gefitinib;gemtuzumab; trastuzumab; gefitinib; ixabepilone; lapatinib;lenalidomide; aminolevulinic acid; temozolomide; nelarabine; sorafenib;nilotinib; pegaspargase; pemetrexed; rituximab; dasatinib; thalidomide;bexarotene; temsirolimus; bortezomib; 244rimethylam; oprozomib;vorinostat; capecitabine; zoledronic acid; anastrozole; sunitinib;aprepitant and nelarabine, or a pharmaceutically acceptable saltthereof.

Additional pharmaceutically active compounds/agents that can be used inthe treatment of cancers and that can be used in combination with one ormore compound of the present invention include: epoetin alfa;darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim;denosumab; ancestim; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG951; and AMG 706, or a pharmaceutically acceptable salt thereof.

In certain claims, a composition provided herein is conjointlyadministered with a chemotherapeutic agent. Suitable chemotherapeuticagents may include, natural products such as vinca alkaloids (e.g.,vinblastine, vincristine, and vinorelbine), paclitaxel,epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics(e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin), mitomycin, enzymes (e.g., L-asparaginase whichsystemically metabolizes L-asparagine and deprives cells which do nothave the capacity to synthesize their own asparagine), antiplateletagents, antiproliferative/antimitotic alkylating agents such as nitrogenmustards (e.g., mechlorethamine, cyclophosphamide and analogs,melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g.,hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., seliciclib,UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638,and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazinine(DTIC), antiproliferative/antimitotic antimetabolites such as folic acidanalogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil,floxuridine, and cytarabine), purine analogs and related inhibitors(e.g., mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole,exemestane, and letrozole), and platinum coordination complexes (e.g.,cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g.,trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamicacid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTorinhibitors (e.g., temsirolimus, everolimus, ridaforolimus, andsirolimus), KSP(Eg5) inhibitors (e.g., Array 520), DNA binding agents(e.g., Zalypsis), PI3K delta inhibitor (e.g., GS-1101 and TGR-1202),PI3K delta and gamma inhibitor (e.g., CAL-130), multi-kinase inhibitor(e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormoneagonists such as leutinizing hormone releasing hormone (LHRH) agonists(e.g., goserelin, leuprolide and triptorelin), BAFF-neutralizingantibody (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors,anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN 163L),aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonalantibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab),inhibitors of KRAS including covalent inhibiors of KRAS G12C, MEKinhibitor, including trametinib, HSP90 inhibitors (e.g., 17 AAG and KOS953), PI3K/Akt inhibitors (e.g., perifosine), Akt inhibitor (e.g.,GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g.,Zamestra™), anti-CD138 (e.g., BT062), Torc1/2 specific kinase inhibitor(e.g., INK128), kinase inhibitor (e.g., GS-1101), ER/UPR targeting agent(e.g., MKC-3946), cFMS inhibitor (e.g., ARRY-382), JAK1/2 inhibitor(e.g., CYT387), PARP inhibitor (e.g., olaparib and veliparib (ABT-888)),BCL-2 antagonist. Other chemotherapeutic agents may includemechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene,gemcitabine, navelbine, sorafenib, or any analog or derivative variantof the foregoing.

The compounds of the present invention may also be used in combinationwith radiation therapy, hormone therapy, surgery and immunotherapy,which therapies are well known to those skilled in the art.

In certain claims, a pharmaceutical composition provided herein isconjointly administered with a steroid. Suitable steroids may include,but are not limited to, 21-acetoxypregnenolone, alclometasone,algestone, amcinonide, beclomethasone, betamethasone, budesonide,chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacort, desonide, desoximetasone,dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone,fluazacort, flucloronide, flumethasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone,fluorometholone, fluperolone acetate, fluprednidene acetate,fluprednisolone, flurandrenolide, fluticasone propionate, formocortal,halcinonide, halobetasol propionate, halometasone, hydrocortisone,loteprednol etabonate, mazipredone, medrysone, meprednisone,methylprednisolone, mometasone furoate, paramethasone, prednicarbate,prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodiumphosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone hexacetonide, and salts and/or derivatives thereof. In aparticular Claim, the compounds of the present invention can also beused in combination with additional pharmaceutically active agents thattreat nausea. Examples of agents that can be used to treat nauseainclude: dronabinol; granisetron; metoclopramide; ondansetron; andprochlorperazine; or a pharmaceutically acceptable salt thereof.

As one aspect of the present invention contemplates the treatment of thedisease/conditions with a combination of pharmaceutically activecompounds that may be administered separately, the invention furtherrelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof the present invention, and a second pharmaceutical compound. The kitcomprises a container for containing the separate compositions such as adivided bottle or a divided foil packet. Additional examples ofcontainers include syringes, boxes, and bags. In some Claims, the kitcomprises directions for the use of the separate components. The kitform is particularly advantageous when the separate components arepreferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing health care professional.

The compounds of the present invention can be administered aspharmaceutically acceptable salts, esters, amides or prodrugs. The term“salts” refers to inorganic and organic salts of compounds of thepresent invention. The salts can be prepared in situ during the finalisolation and purification of a compound, or by separately reacting apurified compound in its free base or acid form with a suitable organicor inorganic base or acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts, and the like. The salts mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to, ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, 247rimethylamine,ethylamine, and the like. See, for example, S. M. Berge, et al.,“Pharmaceutical Salts,” J Pharm Sci, 66: 1-19 (1977).

The term “prodrug” means compounds that are transformed in vivo to yielda compound of the present invention. The transformation may occur byvarious mechanisms, such as through hydrolysis in blood. A discussion ofthe use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugsas Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, andin Bioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

To illustrate, if the compound of the invention contains a carboxylicacid functional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈ alkyl, (C₂—Cl₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-3)alkyl.

Similarly, if a compound of the present invention comprises an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,a-amino(C₁-C₄)alkanoyl, arylacyl and a-aminoacyl, ora-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, —P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

The compounds of the present invention may contain asymmetric or chiralcenters, and therefore, exist in different stereoisomeric forms. It iscontemplated that all stereoisomeric forms of the compounds as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention contemplates all geometricand positional isomers. For example, if the compound contains a doublebond, both the cis and trans forms (designated as Z and E,respectively), as well as mixtures, are contemplated.

Mixture of stereoisomers, such as diastereomeric mixtures, can beseparated into their individual stereochemical components on the basisof their physical chemical differences by known methods such aschromatography and/or fractional crystallization. Enantiomers can alsobe separated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,an alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater (hydrate), ethanol, and the like. The present inventioncontemplates and encompasses both the solvated and unsolvated forms.

It is also possible that compounds of the present invention may exist indifferent tautomeric forms. All tautomers of compounds of the presentinvention are contemplated. Those skilled in the art will recognize thatthe compound names and structures contained herein may be based on aparticular tautomer of a compound. While the name or structure for onlya particular tautomer may be used, it is intended that all tautomers areencompassed by the present invention, unless stated otherwise.

It is also intended that the present invention encompass compounds thatare synthesized in vitro using laboratory techniques, such as those wellknown to synthetic chemists; or synthesized using in vivo techniques,such as through metabolism, fermentation, digestion, and the like. It isalso contemplated that the compounds of the present invention may besynthesized using a combination of in vitro and in vivo techniques.

The compounds of the present invention may exist in various solid statesincluding crystalline states and as an amorphous state. The differentcrystalline states, also called polymorphs, and the amorphous states ofthe present compounds are contemplated as part of this invention.

EXAMPLES

The examples presented below illustrate specific Claims of the presentinvention. These examples are meant to be representative and are notintended to limit the scope of the Claims in any manner.

The following abbreviations may be used herein:

-   -   ˜ about    -   Ac acetate    -   AC₂O acetic anhydride    -   AcOH acetic acid    -   Al₂O₃ aluminum oxide    -   br broad    -   Boc tert-butyloxycarbonyl    -   B(OiPr)₃ triisopropyl borate    -   B(Oallyl)₃ triallyl borate    -   B(OCH₂CF₃)₃ tris(2,2,2-trifluoroethyl) borate    -   B(On-Bu)₃ tri-n-butyl borate    -   Calcd calculated    -   CO₂ carbon dioxide    -   CSA 10-camphorsulfonic acid    -   d day or doublet    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCE dichloroethane    -   DCM dichloromethane    -   DEA diethylamine    -   Dess-Martin periodinane        1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one    -   DIPEA or DIEA diisopropylethylamine    -   DMA N,N-dimethylacetamide    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   EDC N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide    -   ee or e.e. enantiomeric excess    -   ELISA enzyme-linked immunosorbent assay    -   eq or equiv equivalent    -   ESI or ES electrospray ionization    -   Et ethyl    -   Et₂O diethyl ether    -   EtOAc ethyl acetate    -   Et₃N triethylamine    -   EtOH ethyl alcohol    -   EtI ethyl iodide    -   g gram(s)    -   GC gas chromatography    -   h hour(s)    -   H₂ hydrogen gas    -   HCl hydrochloric acid    -   ¹H NMR proton nuclear magnetic resonance spectroscopy    -   HATU        1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   H₂O water    -   HPLC high performance liquid chromatography    -   H₂SO₄ sulfuric acid    -   Hz Hertz    -   IP intraperitoneal    -   IPA isopropyl alcohol    -   K₂CO₃ potassium carbonate    -   KF Karl Fischer titration    -   KHMDS potassium hexamethyldisilazide    -   KOAc potassium acetate    -   KOH potassium hydroxide    -   K₃PO₄ potassium phosphate    -   KOtBu potassium tert-butoxide    -   L liter    -   LAH lithium aluminium hydride    -   LCMS, LC-MS, or LC/MS liquid chromatography mass spectrometry    -   LHMDS lithium hexamethyldisilazide    -   m multiplet    -   mm millimeter    -   M molar (mol/L) or mass    -   Me methyl    -   MeCN acetonitrile    -   Mel iodomethane    -   MeOH methyl alcohol    -   MeTHF 2-methyltetrahydrofuran    -   Me₃SI trimethylsulfonium iodide    -   MeNH₂ methylamine    -   Me₂NH dimethylamine    -   mg milligram(s)    -   MgSO₄ magnesium sulphate    -   MHz megahertz    -   μm micrometer    -   μL microliter    -   min minute(s)    -   mL milliliter(s)    -   mm millimeter(s)    -   mol mole    -   MS mass spectrometry    -   MSA methanesulfonic acid    -   MsCl methanesulfonyl chloride    -   MTBE methyl tert-butyl ether    -   m/z mass-to-charge ratio    -   N Normality (Eq/L)    -   N₂ nitrogen gas    -   nBuLi n-butyllithium    -   NaCl sodium chloride    -   Na₂CO₃ sodium carbonate    -   NaHCO₃ sodium bicarbonate    -   NaH₂PO₄ sodium dihydrogen phosphate    -   NaNO₂ sodium nitrite    -   NaOH sodium hydroxide    -   NaOtBu sodium tert-butoxide    -   Na₂SO₄ sodium sulfate    -   Na₂S₂O₃ sodium thiosulfate    -   NH₃ ammonia, azane    -   NH₄Cl ammonium chloride    -   NH₄OH ammonium hydroxide    -   NMP 1-methyl-2-pyrrolidinone    -   NMR nuclear magnetic resonance spectroscopy    -   OMe methoxy    -   PO per oral    -   +ve positive    -   Ph phenyl    -   PhMe toluene    -   PMB p-methoxybenzyl    -   POCl₃ phosphoryl chloride    -   ppm parts per million    -   Prep preparative    -   psi pounds per square inch    -   q quartet    -   QD once daily    -   QNMR quantitative NMR    -   Rac racemic    -   RBF round-bottomed flask    -   RT, rt, or r.t. room temperature    -   s singlet    -   sat. or satd or sat'd saturated    -   SFC supercritical fluid chromatography    -   SIMes        1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene    -   SiO₂ silica    -   SOCl₂ thionyl chloride    -   t triplet    -   TBDPS tert-butyldiphenylsilyl    -   TBS tert-butyldimethylsilyl    -   TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl    -   t-BuOH tert-butanol    -   TFA triflouroacetic acid    -   THF tetrahydrofuran    -   Ti(OiPr)₄ titanium isopropoxide    -   TLC thin layer chromatography    -   TsOH toluene sulfonic acid    -   UV ultraviolet    -   v/v volume per volume    -   wt% weight percent

It is noted that when a percent (%) is used with regard to a liquid, itis a percent by volume with respect to the solution. When used with asolid, it is the percent with regard to the solid composition.

GENERAL SYNTHETIC SCHEMES

Unless otherwise stated, starting materials and reagents used inpreparing these compounds are either available from commercial supplierssuch as Aldrich Chemical Co., (Milwaukee, Wis.) or are prepared bymethods known to those skilled in the art following procedures set forthin references such as Fieser and Fieser's Reagents for OrganicSynthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry ofCarbon Compounds, Volumes 1-5 and Supplementals (Elsevier SciencePublishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons,1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4thEdition) and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

The starting materials for the following synthetic methods can be foundin the General Methods and General Synthesis for Intermediates. Thesynthesis of some of the starting materials and the intermediates aredisclosed in U.S. Pat. No. 9,562,061 and PCT/US17/19336, respectively,herein incorporated by reference in their entireties for all purposes.These synthetic methods are merely illustrative of some methods by whichthe compounds of this invention can be synthesized, and variousmodifications to these methods can be made and will be suggested to oneskilled in the art having referred to this disclosure. The startingmaterials and the intermediates, and the final products of the reactionmay be isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., more preferably from about 0° C. to about 125° C.and most preferably at about room (or ambient) temperature, e.g., about22° C.

IUPAC names were generated using either ACD/Name v2015 or ChemBioDrawUltra 12.

Example 1(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2‘’-oxiran]-15′-one 13′,13′-dioxide

A 250 mL 3-neck, equipped with a thermocouple, nitrogen inlet andseptum, was charged with(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (10.05 g, 15.48 mmol) and trimethylsulfonium iodide(4.79 g, 23.47 mmol). Dimethyl sulfoxide (80 mL) and tetrahydrofuran (20mL) were added and the reaction was cooled to 5° C. using an ice-waterbath. The reaction was treated with 1 M potassium t-butoxide in THF(39.0 mL, 39.0 mmol) via syringe over a period of 20 min. The reactionwas quenched with glacial acetic acid (2.20 mL, 38.1 mmol) and stirredfor 1 min. The mixture was poured into isopropyl acetate (200 mL) andwashed with water (200 mL). The aqueous layer was extracted withisopropyl acetate (100 mL) and the combined organic layers were washedwith water (3×200 mL), brine (60 mL) and dried over Na₂SO₄. The solutionwas filtered and the filtrate was concentrated under reduced pressure.The residue was azeotrope with DCM (2×200 mL) then dissolved in DCM (40mL). Heptane (400 mL) was added dropwise over a period of 1 h and themixture was then stirred for 30 min. The solids were filtered and driedwith nitrogen purge on the frit for 3 h to give 8.60 g of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-oxiran]-15′-one13′,13′-dioxide as a white solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δppm 8.08 (s, 1H), 7.72 (d, J=8.41 Hz, 1H), 7.22 (d, J=0.98 Hz, 1H), 7.19(dd, J=8.41, 2.35 Hz, 1H), 7.09 (d, J=2.15 Hz, 1H), 6.83-6.95 (m, 2H),5.73-5.91 (m, 1H), 5.60 (d, J=15.26 Hz, 1H), 4.20 (q, J=7.24 Hz, 1H),4.01-4.14 (m, 2H), 3.92 (dd, J=15.45, 4.50 Hz, 1H), 3.73 (br d, J=14.28Hz, 1H), 3.20 (d, J=14.28 Hz, 1H), 2.96 (dd, J=15.55, 6.55 Hz, 1H),2.65-2.85 (m, 2H), 2.47 (d, J=5.48 Hz, 1H), 2.25-2.43 (m, 2H), 1.73-2.08(m, 9H), 1.60-1.72 (m, 1H), 1.33-1.44 (m, 4H), 1.03 (br d, J=5.87 Hz,3H).

Step 2:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A 1 L 3-neck, equipped with a thermocouple, nitrogen adapter and septum,was charged with(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-oxiran]-15′-one13′,13′-dioxide (10.22 g, 16.72 mmol) and 2-methyltetrahydrofuran (300mL). Triethyl borate (50 mL, 291 mmol) was added via syringe and thereaction was placed on a heat block preheated to 65° C. After 12 h thereaction was cooled to room temperature overnight. The reaction mixturewas quenched with saturated NaHCO₃(100 mL) and stirred for 10 min. Theaqueous layer was extracted with EtOAc (3×50 mL) and the combinedorganic layers were washed with brine (50 mL), dried over Na₂SO₄ andfiltered. The filtrate was evaporated onto silica gel and purified byflash chromatography (Isco (330 gram)) eluting with 0.3% AcOH in EtOAc:0.3% AcOH in heptane (0:1→1:1) to afford 6.27 g of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide. MS (ESI, +ve ion) m/z 657.3 (M+1)⁺.

Step 3:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

A 250 mL 3-neck, equipped with a thermocouple, nitrogen adapter andseptum, was charged with the starting(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (6.27 g, 7.54 mmol), DCM (50 mL) and dimethyl sulfoxide(20 mL). The solution was cooled (0° C.) in an ice bath, andN,N-diisopropylethylamine was added (6.6 mL, 37.8 mmol) followed bysulfur trioxide pyridine complex (3.02 g, 18.97 mmol), portion wise over15 min. The ice bath was removed and allowed to warm to room temperaturefor 2 h. The reaction mixture was poured into isopropyl acetate (200 mL)and the solution was washed with water (200 mL). The aqueous layer wasextracted with EtOAc (1×100 mL) and the combined organic layers werewashed with 50% saturated NH₄Cl (2×100 mL), water (50 mL), brine (50 mL)and dried over Na₂SO₄. The solution was filtered and the filtrate wasconcentrated under reduced pressure to give a light-yellow solid. Thesolid was dissolved in EtOAc, evaporated onto silica gel and purified byflash chromatography (Isco (220 gram)) eluting with 0.3% AcOH in EtOAc:0.3% AcOH in heptane (0:1→1:1) to give 4.44 g of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 655.3 (M+1)⁺.

Step 4:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Preparation of amine free base: To a room temperature suspension of(S)-octahydropiperazino[2,1-c]morpholine dihydrochloride (7.04 g, 32.7mmol; Synthonix, Wake Forest, N.C.) in DCM (100 mL) was added sodiummethoxide (25 wt % solution in methanol, 15 mL, 65.6 mmol) and thereaction was stirred for 2 h. The solvent was removed under reducedpressure and the residue was stirred over EtOAc (100 mL) for 1 h. Thesolution was filtered and the filtrate was concentrated under reducedpressure to give (S)-octahydropyrazino[2,1-c][1,4]oxazine (4.33 g) as alight-yellow oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 3.70-3.82(m, 1H), 3.61-3.67 (m, 1H), 3.52-3.60 (m, 1H), 3.15 (t, J=10.47 Hz, 1H),2.79-2.93 (m, 2H), 2.60-2.71 (m, 2H), 2.55 (br d, J=11.54 Hz, 1H),2.27-2.39 (m, 2H), 2.05-2.21 (m, 2H).

To a room temperature solution of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (4.44 g, 6.51 mmol) in 1,2-dichloroethane (40 mL) wasadded a solution of (S)-octahydropyrazino[2,1-c][1,4]oxazine (2.91 g,18.01 mmol) in 1,2-dichloroethane (5 mL) and the reaction was stirredfor 2 h. To the reaction was added sodium triacetoxyborohydride (0.350g, 1.651 mmol) was added as a solid. Additional sodiumtriacetoxyborohydride (0.350 g, 1.651 mmol) was added until the reactionwas complete. The reaction was quenched with saturated NH₄Cl (40 mL) andthe layers were separated. The aqueous layer was extracted with DCM (2×)and the combined organic layers were washed with 1 M KH₂PO₄ (40 mL). Theorganic layer was dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure and stored in the freezer. Theresidual material was dissolved in DCM, evaporated onto silica gel, andpurified by flash chromatography (Isco (330 gram)) eluting withEtOAc:heptane:MeOH:DCM (0:1:0:0→3:2:0:0→0:0:1:49→0:0:3:47) to give 3.63g (70%) of an off-white solid. The material was stirred over MeOH (15mL) for 1 h. To the thick slurry was added MeOH (30 mL) to maintain goodstirring. After another 1 h the solvent was removed under reducedpressure and the residue was dried in vacuo. The solid was dried undernitrogen purge/vacuum for 24 h to give 3.10 g of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 781.3 (M+1)⁺. ¹HNMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.72 (d, J=8.41 Hz, 1H), 7.23(s, 1H), 7.17 (dd, J=8.41, 1.96 Hz, 1H), 7.09 (d, J=1.96 Hz, 1H), 6.89(s, 2H), 5.58-5.75 (m, 1H), 5.43 (br d, J=15.85 Hz, 1H), 4.15 (q, J=6.85Hz, 1H), 4.07 (s, 2H), 4.01 (br d, J=15.45 Hz, 1H), 3.74-3.82 (m, 1H),3.71 (br d, J=14.08 Hz, 1H), 3.54-3.66 (m, 3H), 3.43-3.52 (m, 1H), 3.27(d, J=14.28 Hz, 1H), 3.17 (br t, J=10.37 Hz, 1H), 2.89-3.03 (m, 2H),2.72-2.85 (m, 2H), 2.58-2.71 (m, 2H), 2.54 (m, 2H), 2.48 (br d, J=14.28Hz, 1H), 2.20-2.40 (m, 5H), 2.03-2.20 (m, 4H), 1.65-2.00 (m, 6H),1.54-1.64 (m, 2H), 1.41 (d, J=7.24 Hz, 3H), 1.30-1.38 (m, 4H), 1.01 (brd, J=5.67 Hz, 3H).

Example 2(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a room temperature solution of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.050 g, 0.076 mmol) in 1,2-dichloroethane (1 mL) wasadded 1-(oxetan-3-yl)piperazine (0.100 mL, 0.823 mmol, Astatech, Inc.,Bristol Pa.) via syringe and the reaction was stirred for 1 h. To thereaction was added sodium triacetoxyborohydride (0.050 g, 0.236 mmol) asa solid and the reaction was stirred overnight. The reaction wasquenched with pH 7 buffer and the layers were separated. The aqueouslayer was extracted with DCM (3×) and the combined organic layers wereconcentrated under reduced pressure. The residue was dissolved in MeOHand purified by reverse-phase HPLC (Gilson; Gemini-NX 10 m C18 110 ÅAXIA, 100×50 mm column) eluting with 0.1% TFA-H₂O:0.1% TFA CH₃CN(7:3→5:95). The fractions containing the desired product were combined,treated with pH 7 buffer (1 M KH₂PO₄/1 M K₂HPO₄; 5 mL) and the layerswere separated. The aqueous layer was extracted with EtOAc (3×) and thecombined organic layers were washed with brine and dried over Na₂SO₄.The solution was filtered and concentrated under reduced pressure togive(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (47 mg, 79%) as a white crystalline solid. MS (ESI, +veion) m/z 781.2 (M+1)⁺. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 8.07(br s, 1H), 7.71 (d, J=8.41 Hz, 1H), 7.23 (s, 1H), 7.17 (dd, J=8.51,2.25 Hz, 1H), 7.08 (d, J=2.15 Hz, 1H), 6.82-6.93 (m, 2H), 5.61-5.78 (m,1H), 5.45 (br d, J=15.85 Hz, 1H), 4.56-4.66 (m, 2H), 4.44-4.54 (m, 2H),4.15 (br d, J=7.04 Hz, 1H), 4.03-4.10 (m, 2H), 3.99 (br d, J=14.67 Hz,1H), 3.70 (br d, J=14.28 Hz, 1H), 3.61 (quin, J=7.24 Hz, 1H), 3.35-3.52(m, 2H), 3.26 (d, J=14.28 Hz, 1H), 2.95 (br dd, J=14.87, 9.98 Hz, 1H),2.72-2.85 (m, 2H), 2.59-2.71 (m, 2H), 2.46-2.57 (m, 4H), 2.24-2.41 (m,4H), 2.02-2.19 (m, 4H), 1.78-1.98 (m, 3H), 1.70 (br s, 1H), 1.57 (br d,J=6.26 Hz, 4H), 1.29-1.45 (m, 7H), 1.00 (br d, J=5.09 Hz, 3H).

Example 3(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-(1,3-DITHIAN-2-YL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-(1,3-DITHIAN-2-YL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To a 250 mL round-bottomed flask was added 1,3-dithiane (4.79 g, 39.8mmol) and THF (100 mL). The mixture was cooled to −78° C. andn-butyllithium (1.6 M solution in hexane, 22.5 mL, 36.1 mmol) was addedover 8 min. The solution was stirred in the −78° C. bath for 30 min. Ina separate 100 mL flask was added(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide and THF (5 mL). To this was added lanthanum(III)chloride bis(lithium chloride) complex solution (0.6 M in THF, 60.1 mL,36.1 mmol) and this was stirred for 5 min at room temperature. Thesolution was then cooled to −78° C. and added via cannula to thedithiane solution. After 2.5 h at −78° C., the solution was treated withsat NH₄Cl and water. The pH of the solution was adjusted to pH=4 withaqueous 10% citric acid and aqueous NaHCO₃. The solution was extractedwith EtOAc and the combined extracts were filtered through Celite. Thefiltrate was washed with water and brine and then dried (Na₂SO₄) andconcentrated to afford a mixture of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a brown oil which was carried on directly to nextstep. MS (ESI, +ve ion) m/z 717.5 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-(1,3-DITHIAN-2-YL)-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-(1,3-DITHIAN-2-YL)-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To a resealable vial was added the mixture of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (6.81 g, 9.49 mmol) and THF (100 mL). The mixture wascooled to 0° C. and potassium bis(trimethylsilyl)amide (1 M in THF, 38.0mL, 38.0 mmol) was added over 10 min. The solution was stirred at 0° C.for 5 min and then iodomethane (2.36 mL, 38.0 mmol) was added over 3min. After 2.5 h at 0° C., the solution was poured into saturated NH₄Cland the pH was adjusted to 4 with 1 M citric acid. The solution wasextracted with EtOAc and the combined extracts were washed with brine,dried (Na₂SO₄) and concentrated onto silica. Purification by silica gelchromatography (0% to 35% EtOAc/heptane, both with 0.3% AcOH v/v, 330 gRedi-Sep Gold column) afforded:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (1.66 g, 2.27 mmol, 24% yield). MS (ESI, +ve ion) m/z731.5 (M+H)⁺ and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (4.69 g, 6.41 mmol, 68% yield). MS (ESI, +ve ion) m/z731.5 (M+H)⁺.

Step 3:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

To a 250 mL round-bottomed flask equipped with a reflux condenser wasadded(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (1.63 g, 2.23 mmol), acetonitrile (40 mL) and water (10mL). The mixture was heated to 50° C. and calcium carbonate (1.12 g,11.1 mmol) and iodomethane (1.38 mL, 22.3 mmol) were added. After 23 hat 50° C., the solution was poured into sat NH₄Cl and water and thenextracted with EtOAc. The combined extracts were washed with brine andthen dried (Na₂SO₄) and concentrated onto silica. Purification by silicagel chromatography (0% to 40% EtOAc/heptane (both with 0.3% AcOH),Silicycle HP 120 g column) afforded(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (1.34 g, 2.09 mmol, 94% yield) as a white solid. MS(ESI, +ve ion) m/z 641.3 (M+H)⁺.

Step 4:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-((4-(3-OXETANYL)-1-PIPERAZINYL)METHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To a resealable vial was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.135 g, 0.211 mmol), 1,2-dichloroethane (2.0 mL) and1-(oxetan-3-yl)piperazine (0.090 g, 0.632 mmol, AstaTech, Inc.). Thesolution was stirred at room temperature for 1 h. To this solution wasadded sodium triacetoxyborohydride (0.011 g, 0.053 mmol). After stirringovernight at room temperature, additional portions of sodiumtriacetoxyborohydride (0.011 g, 0.053 mmol) were added until thereaction was complete. The reaction was carefully quenched with MeOHstirred for 1 h and then filtered for Prep-HPLC purification. Thesolution was purified by prep-HPLC (Column: Phenomenex Luna 5μ C18, 100Å, 150×20 mm; Solvent: A=water (0.1% TFA), B=(R) (0.1% TFA), 30 mL/min,30% B to 100% B over 18 min then 2 min at 100% B) and the fractionscontaining product were treated with aqueous pH 7 buffer (KH₂PO₄/K₂HPO₄based) and extracted with EtOAc. The combined extracts were washed withbrine, and then dried (Na₂SO₄), filtered and concentrated to afford(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a white solid (0.101 g, 0.132 mmol, 63% yield). ¹HNMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.72 (d, J=9.8 Hz, 1H), 7.25 (brs, 1H), 7.16 (br d, J=8.6 Hz, 1H), 7.09 (s, 1H), 6.89 (s, 2H), 5.62 (brs, 1H), 5.37 (br d, J=14.9 Hz, 1H), 4.56-4.66 (m, 2H), 4.52 (br t, J=5.9Hz, 2H), 4.12 (br d, J=6.5 Hz, 1H), 4.06 (s, 2H), 3.98 (br d, J=14.9 Hz,1H), 3.70 (br d, J=14.1 Hz, 1H), 3.40-3.52 (m, 1H), 3.36 (s, 3H),3.19-3.30 (m, 1H), 2.90-3.03 (m, 1H), 2.64-2.85 (m, 4H), 2.45-2.63 (m,5H), 2.26-2.41 (m, 4H), 2.15-2.25 (m, 1H), 2.02-2.15 (m, 3H), 1.78-1.99(m, 4H), 1.66-1.76 (m, 1H), 1.49-1.64 (m, 2H), 1.40 (br d, J=7.2 Hz,4H), 1.01 (br d, J=5.7 Hz, 3H). MS (ESI, +ve ion) m/z 767.3 (M+H)⁺.

Example 4(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-((9AS)-HEXAHYDROPYRAZINO[2,1-C][1,4]OXAZIN-8(1H)-YLMETHYL)-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To a 100 mL 3-neck flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.486 g, 0.758 mmol), DCM (20 mL) and ethanol (8.0 mL).To this solution was added (9aS)-octahydropiperazino[2,1-c]morpholinedihydrochloride (1.96 g, 9.10 mmol) followed byN,N-diisopropylethylamine (4.0 mL, 22.7 mmol). To the solution was addedtitanium(iv) isopropoxide (2.24 mL, 7.58 mmol). The solution was stirredat room temperature for 17 h. To this solution was added sodiumborohydride (0.143 g, 3.79 mmol) in 3 portions. The reaction mixture wasstirred at room temperature. After 18 h, additional sodium borohydride(35 mg) was added and stirring was continued at room temperature for anadditional 24 h. The reaction was carefully quenched with sat. NH₄Cl andthen diluted with aqueous pH 7 buffer (KH₂PO₄/K₂HPO₄ based), filteredthrough Celite, and extracted with EtOAc. The combined extracts werewashed with brine, dried (Na₂SO₄), filtered and concentrated to afford awhite solid. The solid was purified by prep-HPLC (Column: PhenomenexGemini C18 110 Å, 100×50 mm; Solvent: A=water (0.1% TFA), B=(R) (0.1%TFA), 100 mL/min, 10% B to 100% B over 11 min then 2 min at 100% B) andthe fractions containing product were treated with aqueous pH 7 buffer(KH₂PO₄/K₂HPO₄ based), concentrated to remove the acetonitrile, andextracted with EtOAc. The combined extracts were washed with brine,dried (Na₂SO₄), filtered and concentrated to afford(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a white solid (0.478 g, 0.622 mmol, 82% yield). ¹HNMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.72 (d, J=8.6 Hz, 1H), 7.26 (s,1H), 7.17 (dd, J=8.5, 2.2 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.85-6.93 (m,2H), 5.57-5.68 (m, 1H), 5.35 (s, 1H), 4.08-4.17 (m, 1H), 4.07 (s, 2H),3.96-4.04 (m, 1H), 3.78 (br d, J=9.6 Hz, 1H), 3.70 (br d, J=14.3 Hz,1H), 3.59 (br d, J=10.8 Hz, 2H), 3.35 (s, 3H), 3.25 (d, J=14.3 Hz, 1H),3.17 (br s, 1H), 2.88-3.06 (m, 2H), 2.72-2.81 (m, 2H), 2.58-2.67 (m,2H), 2.45-2.54 (m, 3H), 2.30-2.37 (m, 2H), 2.17-2.27 (m, 3H), 2.07-2.14(m, 2H), 2.03-2.07 (m, 1H), 1.90-1.99 (m, 2H), 1.81-1.90 (m, 2H),1.66-1.75 (m, 1H), 1.48-1.65 (m, 4H), 1.36-1.44 (m, 4H), 1.02 (d, J=6.1Hz, 3H) MS (ESI, +ve ion) m/z 767.7 (M+H)⁺.

Example 5(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-((4-(1-METHYLETHYL)-1-PIPERAZINYL)METHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To a resealable vial was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.135 g, 0.211 mmol), 1,2-dichloroethane (2 mL) and1-isopropylpiperazine (0.090 mL, 0.632 mmol, Across Organics). Thesolution was stirred at room temperature for 1 h. To this solution wasadded sodium triacetoxyborohydride (0.011 g, 0.053 mmol). After 2 h atroom temperature, additional 0.25 eq. portions of sodiumtriacetoxyborohydride were added (4 total) until the reaction wascomplete. The reaction mixture was carefully quenched with MeOH, stirredfor 1 h, and then filtered for Prep-HPLC purification. The solution waspurified by prep-HPLC (Column: Phenomenex Luna C18, 100 Å, 150×21.20 mm;Solvent: A=water (0.1% TFA), B=(R) (0.1% TFA), 30 mL/min, 30% B to 100%B over 18 min then 2 min at 100% B) and the fractions containing productwere treated with aqueous pH 7 buffer (KH₂PO₄/K₂HPO₄ based) andextracted with EtOAc. The combined extracts were washed with brine, andthen dried (Na₂SO₄), filtered and concentrated to afford(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a white solid (0.0855 g, 0.113 mmol, 54% yield). ¹HNMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.76 (d, J=8.6 Hz, 1H), 7.30 (s,1H), 7.20 (br d, J=8.4 Hz, 1H), 7.13 (s, 1H), 7.00 (d, J=8.2 Hz, 1H),6.92 (d, J=9.0 Hz, 1H), 5.63-5.74 (m, 1H), 5.49 (d, J=15.8 Hz, 1H), 4.10(s, 2H), 3.96-4.05 (m, 2H), 3.74 (br d, J=14.3 Hz, 1H), 3.46 (s, 1H),3.38-3.43 (m, 1H), 3.37 (s, 3H), 3.30 (br d, J=14.3 Hz, 1H), 2.96-3.04(m, 2H), 2.85-2.94 (m, 2H), 2.77-2.84 (m, 2H), 2.54-2.68 (m, 3H),2.36-2.43 (m, 1H), 2.23-2.35 (m, 2H), 2.14-2.23 (m, 2H), 2.06-2.14 (m,2H), 1.83-2.03 (m, 4H), 1.50-1.76 (m, 4H), 1.35-1.47 (m, 10H), 1.05 (d,J=6.7 Hz, 3H). MS (ESI, +ve ion) m/z 753.2 (M+H)⁺.

Example 6(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-((4-TERT-BUTYL-1-PIPERAZINYL)METHYL)-6-CHLORO-7′-ETHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To a resealable vial was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide, 0.035 g, 0.053 mmol), 1,2-dichloroethane (0.7 mL) andN-t-butylpiperazine (0.026 mL, 0.160 mmol, Oakwood Products, Inc.). Thesolution was stirred at room temperature for 30 min. To this solutionwas added sodium triacetoxyborohydride (2.83 mg, 0.013 mmol.). Thereaction was stirred at room temperature. After 1 h, additional portionsof sodium triacetoxyborohydride (2.83 mg, 0.013 mmol) were added every 1h until the reaction was complete. The reaction was carefully quenchedwith MeOH, stirred for 30 min and then concentrated. Purification bysilica gel chromatography (0% to 10% MeOH/CH₂Cl₂) afforded(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-((4-tert-butyl-1-piperazinyl)methyl)-6-chloro-7′-ethoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a white solid (0.0284 g, 0.036 mmol, 68% yield). ¹HNMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.73 (d, J=8.6 Hz, 1H), 7.31 (s,1H), 7.16 (dd, J=8.5, 2.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 7.02 (br d,J=8.0 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 5.55-5.74 (m, 2H), 3.96-4.10 (m,3H), 3.79 (br s, 1H), 3.69 (br d, J=14.5 Hz, 1H), 3.50-3.65 (m, 1H),3.34-3.45 (m, 1H), 3.30 (d, J=14.3 Hz, 1H), 2.94-3.04 (m, 1H), 2.73-2.80(m, 2H), 2.58-2.68 (m, 3H), 2.45-2.57 (m, 3H), 2.29-2.35 (m, 1H),2.03-2.18 (m, 4H), 1.90-1.98 (m, 2H), 1.81-1.90 (m, 2H), 1.55-1.70 (m,3H), 1.45-1.53 (m, 1H), 1.34-1.44 (m, 1H), 1.24-1.31 (m, 9H), 1.17-1.24(m, 9H), 1.00 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 781.3 (M+H)⁺.

Example 7(1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-((9AS)-HEXAHYDROPYRAZINO[2,1-C][1,4]OXAZIN-8(1H)-YLMETHYL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE

Step 1:(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-oxiran]-15′-one13′,13′-dioxide

To a stirred solution of(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′,15′-dione13′,13′-dioxide (100 mg, 0.167 mmol) and trimethylsulfoxonium iodide(38.6 mg, 0.175 mmol) in DMSO (1.5 mL) was added potassium hydroxide(33.0 mg, 0.501 mmol) at room temperature. The resulting mixture wasstirred at room temperature for a period of 18 h. The mixture was pouredinto saturated ammonium chloride aqueous solution and extracted withEtOAc (2×). The combined organics were dried over anhydrous sodiumsulfate. The residue was subjected to combi-flash column chromatographyon a 12 g ISCO gold column eluting with 10% to 100% EtOAc/hexanes togive(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-oxiran]-15′-one13′,13′-dioxide (72 mg, 0.117 mmol, 70% yield) as a mixture ofdiastereomers. MS (ESI, +ve ion) m/z 613.1 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide

A mixture of(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-oxiran]-15′-one13′,13′-dioxide (840 mg, 1.37 mmol),(S)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (1.47 g, 6.85mmol), and triethylamine (3.00 mL, 21.6 mmol) in EtOH (6.0 mL) in asealed microwave reaction vessel was subjected to microwave reactioncondition (24 h, 90° C.). The crude mixture was directly loaded onto asilica gel precolumn (25 g) and subjected to combi-flash columnchromatography on a 12 g ISCO gold column eluting with 0% to 20%MeOH/DCM to give an impure mixture of two epimeric beta-hydroxylamineproducts, which was subjected to separation by SFC (Column: MSA, MobilePhase: 65:35 (A:B) isocratic, A: Liquid CO₂, B: methanol (20 mM NH₃),Flow Rate: 70 g/min, Column/Oven temp.: 40° C., Detection: UV at 240nm). The epimer first eluting on both the reverse-phase prep-HPLC andthe SFC column was collected and subjected to combi-flash columnchromatography on a 12 g ISCO gold column eluting with 0 to 20% MeOH/DCMto give(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (340 mg, 0.45 mmol, 33% yield) as a white solid. ¹H NMR(400 MHz, DICHLOROMETHANE-d₂) δ 7.72 (d, J=8.61 Hz, 1H), 7.17 (dd,J=2.15, 8.41 Hz, 1H), 7.09 (d, J=2.15 Hz, 1H), 7.01 (s, 1H), 6.91-6.99(m, 2H), 4.04-4.15 (m, 3H), 3.87 (br d, J=15.06 Hz, 1H), 3.78 (dd,J=2.93, 11.15 Hz, 1H), 3.69 (br d, J=14.28 Hz, 1H), 3.56-3.65 (m, 2H),3.16-3.27 (m, 2H), 3.00 (br dd, J=8.71, 15.16 Hz, 1H), 2.87 (br d,J=9.98 Hz, 1H), 2.59-2.79 (m, 7H), 2.44-2.54 (m, 3H), 2.23-2.41 (m, 4H),1.98-2.12 (m, 3H), 1.87-1.96 (m, 2H), 1.80-1.86 (m, 1H), 1.69-1.78 (m,2H), 1.55 (br dd, J=9.29, 13.79 Hz, 3H), 1.20-1.44 (m, 9H), 0.98 (d,J=6.65 Hz, 3H). MS (ESI, +ve ion) m/z 755.3 (M+H)⁺.

Example 8(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-(((3R)-3-METHYL-4-(1-METHYLETHYL)-1-PIPERAZINYL)METHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

Step 1: (R)-TERT-BUTYL 4-ISOPROPYL-3-METHYLPIPERAZINE-1-CARBOXYLATE

A mixture of (R)-1-boc-3-methyl-piperazine (630 mg, 3.15 mmol) andacetone (3.0 mL, 40.9 mmol) in DCM (4.0 mL) was stirred for 10 minbefore sodium triacetoxyborohydride (1333 mg, 6.29 mmol) was added inone portion as a solid. The resulting mixture was stirred at roomtemperature for 2.5 days. MeOH (0.5 mL) was added to the reaction andthe mixture was stirred for 5 min and then directly loaded onto a silicagel precolumn (25 g) and subjected to combi-flash column chromatographyon a 24 g ISCO gold column eluting with 2% to 20% MeOH/DCM to give(R)-tert-butyl 4-isopropyl-3-methylpiperazine-1-carboxylate (0.72 g,2.97 mmol, 94% yield) as a colorless oil. ¹H NMR (400 MHz,DICHLOROMETHANE-d₂) δ 3.54-3.90 (m, 2H), 3.25 (td, J=6.41, 13.01 Hz,1H), 3.02 (br s, 1H), 2.64-2.84 (m, 2H), 2.52-2.63 (m, 1H), 2.19-2.34(m, 1H), 1.43 (s, 9H), 1.10 (d, J=6.65 Hz, 3H), 1.04 (d, J=6.26 Hz, 3H),0.90 (d, J=6.65 Hz, 3H). MS (ESI, +ve ion) m/z 243.2 (M+H)⁺.

Step 2: (R)-1-ISOPROPYL-2-METHYLPIPERAZINE BIS-TFA SALT

To a stirred solution of (R)-tert-butyl4-isopropyl-3-methylpiperazine-1-carboxylate (670 mg, 2.76 mmol) in DCM(10 mL) was added trifluoroacetic acid (3.0 mL, 40 mmol) at roomtemperature. The resulting mixture was stirred at room temperature for40 min. The volatiles were removed and the residue was subjected to highvacuum to give (R)-1-isopropyl-2-methylpiperazine bis-TFA salt as anoff-white solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 11.33-12.07 (m,2H), 10.45-11.02 (m, 1H), 3.88-4.10 (m, 3H), 3.72-3.86 (m, 2H),3.49-3.65 (m, 3H), 1.46 (dd, J=6.46, 12.91 Hz, 6H), 1.31 (d, J=6.65 Hz,3H). MS (ESI, +ve ion) m/z 143.2 (M+H)⁺.

Step 3:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′,12′-dimethyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a stirred mixture of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (20 mg, 0.031 mmol) and(R)-1-isopropyl-2-methylpiperazine bis-TFA salt (76.2 mg, 0.206 mmol) inDCM (1.5 mL) was added N,N-diisopropylethylamine (0.50 mL, 2.9 mmol).The resulting mixture was stirred at room temperature for 10 min beforesodium triacetoxyborohydride (26.4 mg, 0.125 mmol) was added in oneportion as a solid. The resulting mixture was stirred at roomtemperature for 25 h. The reaction mixture was concentrated in vacuo andthe residue was dissolved and taken up in MeOH and subjected topreparative reverse-phase HPLC (Gemini™ Prep C₁₈ 10 μm column;Phenomenex, Torrance, Calif.; gradient elution of 35 to 90% MeCN inwater, where both solvents contain 0.1% TFA, 15-min gradient in a 24 minmethod) to give, after lyophilization,(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′,12′-dimethyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (17.6 mg, 0.020 mmol, 64% yield) as a TFA salt as awhite solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 8.08 (br s, 1H),7.71 (d, J=8.61 Hz, 1H), 7.11-7.20 (m, 2H), 7.09 (d, J=1.76 Hz, 1H),6.90 (s, 2H), 5.78-5.96 (m, 1H), 5.47 (br d, J=15.65 Hz, 1H), 4.13-4.26(m, 1H), 4.07 (s, 2H), 3.82-3.99 (m, 2H), 3.58-3.77 (m, 2H), 3.20-3.51(m, 9H), 2.92-3.04 (m, 1H), 2.74-2.82 (m, 3H), 2.51-2.62 (m, 2H),2.02-2.18 (m, 6H), 1.85-1.97 (m, 3H), 1.72-1.79 (m, 1H), 1.55-1.68 (m,2H), 1.35-1.45 (m, 10H), 1.24 (d, J=6.85 Hz, 3H), 1.02 (d, J=6.65 Hz,3H). MS (ESI, +ve ion) m/z 767.2 (M+H)⁺.

Example 9(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-ETHOXY-11′,12′-DIMETHYL-7′-(((3R)-3-METHYL-4-(1-METHYLETHYL)-1-PIPERAZINYL)METHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To an 1-dram vial was placed(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (12 mg, 0.018 mmol) followed by a solution of(R)-1-isopropyl-2-methylpiperazine 2,2,2-trifluoroacetate (46.9 mg,0.126 mmol) in DCM (1.5 mL) and N,N-diisopropylethylamine (0.60 mL, 3.5mmol). The resulting mixture was stirred at room temperature for 10 minbefore sodium triacetoxyborohydride (16 mg, 0.073 mmol) was added in oneportion as a solid. The resulting mixture was stirred at roomtemperature for 58 h. The reaction mixture was concentrated in vacuo andthe residue was dissolved and taken up in MeOH and subjected topreparative reverse-phase HPLC (Gemini™ Prep C18 10 μm column;Phenomenex, Torrance, Calif.; gradient elution of 20% to 90% MeCN inwater, where both solvents contain 0.1% TFA, 15-min gradient in a 24 minmethod) to give, after lyophilization,(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-ethoxy-11′,12′-dimethyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (11.2 mg, 0.013 mmol, 70% yield) as a TFA salt as awhite solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 8.05 (br s, 1H),7.71 (d, J=8.61 Hz, 1H), 7.17 (dd, J=2.25, 8.51 Hz, 1H), 7.08-7.13 (m,2H), 6.90 (s, 2H), 5.94-6.08 (m, 1H), 5.55-5.64 (m, 1H), 4.20-4.29 (m,1H), 4.08 (s, 2H), 3.85-3.92 (m, 2H), 3.70-3.83 (m, 2H), 3.62-3.68 (m,1H), 3.46-3.58 (m, 3H), 3.33 (br d, J=4.50 Hz, 2H), 3.26 (d, J=14.28 Hz,1H), 2.99 (br dd, J=10.07, 14.57 Hz, 2H), 2.73-2.87 (m, 3H), 2.57 (brdd, J=7.92, 14.18 Hz, 2H), 2.11-2.18 (m, 3H), 2.06 (br d, J=13.89 Hz,2H), 1.86-1.98 (m, 4H), 1.79 (br d, J=8.02 Hz, 1H), 1.67 (br d, J=4.89Hz, 2H), 1.37-1.45 (m, 13H), 1.24 (d, J=6.65 Hz, 3H), 1.01 (d, J=6.65Hz, 3H). MS (ESI, +ve ion) m/z 781.2 (M+H)⁺.

Example 10(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-((9AR)-OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN-2-YLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

Step 1:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-7′-((9AR)-OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN-2-YLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

Preparation of amine free base: To a 150 mL round bottomed flask wasadded (R)-octahydro-1H-pyrido[1,2-a]pyrazine dihydrochloride (5.0 g,23.5 mmol, WuXi) and methanol (30 mL). To the solution at roomtemperature was added sodium methoxide (25 wt % solution in methanol,14.0 mL, 58.6 mmol) over 2 min. The solution was stirred at roomtemperature for 10 min and then concentrated. The material was treatedwith 2-methyltetrahydrofuran to form a suspension and then filtered. Thefiltrate was concentrated to form a viscous brown oil. The oil wastreated with 2-methyltetrahydrofuran and heptane, filtered through asyringe filter and then concentrated to afford(R)-octahydro-1H-pyrido[1,2-a]pyrazine (3.4 g) as a brown semi-solid.

To a 250 mL 3-neck flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2‘’-oxiran]-15′-one 13′,13′-dioxide (4.75 g, 7.77 mmol), sodiumtert-butoxide (1.49 g, 15.5 mmol), and 2-methyltetrahydrofuran (40 mL).To the solution was added (R)-octahydro-1H-pyrido[1,2-a]pyrazine (1.64g, 11.7 mmol). The reaction mixture was then heated at 65° C. for 1 d.The solution was allowed to cool to room temperature and treated with pH7 buffer (K₂HPO₄/KH₂PO₄ based). The solution was extracted with DCM (3×)and the combined extracts were washed with water and brine, dried overNa₂SO₄, and concentrated. The crude product,(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide, was carried on directly.

Step 2:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-((9AR)-OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN-2-YLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To a 250 mL flask containing(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (5.8 g, 7.7 mmol) was added 2-methyltetrahydrofuran (80mL). The solution was cooled to 0° C. and potassiumbis(trimethylsilyl)amide (1 M in THF, 19.3 mL, 19.3 mmol) was added over5 min. After stirring for 10 min at 0° C., iodomethane (1.44 mL, 23.2mmol) was added in one portion. The solution was stirred at 0° C. for 2h and then additional potassium bis(trimethylsilyl)amide (4 mL) wasadded, stirred for 10 min and then additional iodomethane (0.48 mL) wasadded. The solution was stirred for 1 h at 0° C. and then aqueous pH 7buffer (KH₂PO₄/K₂HPO₄ based) was added and the reaction mixture wasallowed to warm to room temperature. The solution was extracted with DCM(3×) and the combined extracts were washed with brine, dried overNa₂SO₄, and concentrated onto silica. Purification by silica gelchromatography (10% to 60% EtOAc/heptane and then 5% to 10% MeOH/CH₂Cl₂)afforded(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as an off-white solid (3.30 g, 4.31 mmol, 56% yield). ¹HNMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.72 (d, J=8.6 Hz, 1H), 7.26 (d,J=1.4 Hz, 1H), 7.17 (dd, J=8.6, 2.2 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H),6.92-6.99 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 5.64 (dt, J=15.7, 5.3 Hz,1H), 5.42 (br d, J=16.4 Hz, 1H), 4.07 (s, 2H), 4.03 (br d, J=7.2 Hz,1H), 3.98 (br d, J=14.9 Hz, 1H), 3.70 (br d, J=14.3 Hz, 1H), 3.34 (s,3H), 3.23-3.30 (m, 1H), 3.06-3.22 (m, 2H), 2.90-3.01 (m, 1H), 2.74-2.81(m, 2H), 2.65-2.73 (m, 2H), 2.52-2.62 (m, 4H), 2.28-2.35 (m, 1H),2.16-2.26 (m, 2H), 2.03-2.15 (m, 3H), 1.81-1.99 (m, 6H), 1.71-1.79 (m,2H), 1.57-1.71 (m, 4H), 1.47-1.56 (m, 2H), 1.34-1.44 (m, 5H), 1.02 (d,J=6.7 Hz, 3H). MS (ESI, +ve ion) m/z 765.3 (M+H)⁺.

Example 11(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(3R,4S)-1-methoxy-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide

A dry 2 L three neck flask with a thermo couple and magnetic stir barunder nitrogen was charged with(S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (54 g, 134mmol) and 300 mL of dry toluene. Cooled solution to −76° C. internaltemperature (acetone/dry ice bath). Added n-butyllithium solution (1.6 Min hexanes, 100 mL, 161 mmol) slowly via cannula under a positivepressure of nitrogen. The mixture was stirred at −78° C. for 1 hour.Then 2-bromoethyl methyl ether (18.88 mL, 201 mmol) was slowly viasyringe. After the addition, the −78° C. bath was replaced with an icewater bath. After a total of 105 minutes reaction time, the reaction wasquenched with saturated ammonium chloride at 0° C. The mixture wasdiluted with water and EtOAc and warmed to room temperature withstirring. The layers were separated and extracted with additional EtOAc.The combined organic layers were washed with water and brine, dried oversodium sulfate, filtered, and concentrated in vacuo. The crude productswere further separated to give 20.4 g of(3R,4S)-1-methoxy-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide(44.2 mmol, 55% yield). MS (ESI, +ve ion) m/z 484.0 (M+Na)⁺.

Step 2: (3R,4S)-1-methoxy-4-methylhept-6-ene-3-sulfonamide

At 0° C., trifluoroacetic acid (164 mL, 2210 mmol) was added dropwisevia addition funnel to a solution of(3R,4S)-1-methoxy-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide(20.4 g, 44.2 mmol) and anisole (48.0 mL, 442 mmol) in DCM (221 mL). Thesolution was allowed to come to room temperature and stirred overnight.The reaction was concentrated in vacuo. The remaining material waspartitioned between DCM and saturated aqueous sodium bicarbonate. Thelayers were separated and the aqueous layer was extracted with DCM. Thecombined organic extracts were washed with saturated aqueous sodiumchloride and dried over sodium sulfate. The solution was filtered andconcentrated in vacuo to give the crude material. Purification by flashcolumn chromatography on silica gel (eluted with 0% to 100% EtOAc inheptane) gave (3R,4S)-1-methoxy-4-methylhept-6-ene-3-sulfonamide (9.85g, 44.5 mmol, 101% yield) as a light yellow oil. MS (ESI, +ve ion) m/z243.9 (M+Na)⁺.

Step 3:(S)-5-(((1R,2R)-2-((S)-1-acetoxyallyl)cyclobutyl)methyl)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid

To a nitrogen inerted 3-neck 1 L flask equipped with a thermometer and amagnetic stir bar at room temperature was added 4-(dimethylamino)pyridine (0.821 g, 6.72 mmol), 2-methyltetrahydrofuran (80 mL),triethylamine (7.02 mL, 50.4 mmol), acetic anhydride (4.76 mL, 50.4mmol), and a solution of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (15.72 g, 33.6 mmol) in 2-methyltetrahydrofuran (80 mL) was addedvia cannula over 20 min (internal temperature increased from 20° C. to25° C. during the addition). The reaction mixture was stirred at roomtemperature for 1.5 h. Water (40 mL) was added (internal temperatureincreased from 23° C. to 26° C.) followed by 1 M Na₂HPO₄ (60 mL). Sodiumhydroxide (1 M, 20 mL, 220 mmol) was added until the pH reached 9. Themixture was stirred at room temperature for 19 h and the pH was adjustedto 3 with 2 M HCl (80 mL). The mixture was diluted with PhMe (150 mL)and transferred to a separatory funnel. The aqueous layer was discardedand the organic phase was washed with water (75 mL), 20% brine (75 mL),and concentrated under reduced pressure. The concentrate was dilutedwith PhMe (100 mL) and the PhMe was removed under reduced pressure. Thiswas repeated three times to give(S)-5-(((1R,2R)-2-((S)-1-acetoxyallyl)cyclobutyl)methyl)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid as an orange oil that was used without further purification. MS(ESI, +ve ion) m/z 510.2 (M+H)⁺.

Step 4:(S)-1-((1R,2R)-2-(((S)-6′-chloro-7-((((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)carbamoyl)-3′,4′-dihydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalen]-5(4H)-yl)methyl)cyclobutyl)allylacetate

To a 1 L 3-neck flask was charged(S)-5-(((1R,2R)-2-((S)-1-acetoxyallyl)cyclobutyl)methyl)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (28.73 g, 35.8 mmol) as a solution in toluene (228 mL). DMF (0.277mL, 3.58 mmol) was added followed by slow addition of thionyl chloride(2.74 mL, 37.6 mmol) via syringe. The reaction was stirred at roomtemperature for 4 h and additional thionyl chloride (0.50 mL) was addedand the reaction was stirred for 1 h. In a separate flask(3R,4S)-1-methoxy-4-methylhept-6-ene-3-sulfonamide (9.85 g, 42.5 mmol)and 4-(dimethylamino)pyridine (0.437 g, 3.58 mmol) were combined andazetroped by concentration in vacuo with PhMe (80 mL) and then taken upin 100 mL of PhMe. The resulting solution was added to the acid chloridesolution described above via cannula. The solution was cooled in an icebath for 10 min before triethylamine (17.41 mL, 125 mmol) was addeddropwise via addition funnel. After the addition, the reaction waswarmed to room temperature and stirred overnight. The reaction wasquenched with saturated ammonium chloride. To the mixture was added 0.1M aqueous HCl and then the mixture was extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried with sodiumsulfate, filtered, and concentrate in vacuo. Purification by flashcolumn chromatography on silica gel (eluted with 0% to 100% EtOAc inheptane) gave(S)-1-((1R,2R)-2-(((S)-6′-chloro-7-((((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)carbamoyl)-3′,4′-dihydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalen]-5(4H)-yl)methyl)cyclobutyl)allylacetate (28.11 g, 39.4 mmol) as an orange foam that was used in the nextstep without further purification. MS (ESI, +ve ion) m/z 713.0 (M+H)⁺.

Step 5:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-ylacetate

To a 5 L reactor equipped with mechanical stirrer, thermo couple,nitrogen sparge tube, condenser, was charged 3.6 L of toluene. The PhMewas heated at 79° C. with sparging of nitrogen through the solution. Ina separate flask,(S)-1-((1R,2R)-2-(((S)-6′-chloro-7-((((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)carbamoyl)-3′,4′-dihydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalen]-5(4H)-yl)methyl)cyclobutyl)allylacetate (25.14 g, 32.0 mmol) was azetroped with 300 mL of toluene andthen dissolved in 1.2 L PhMe which was added via syringe pump over 2 h.Simultaneously, 4 charges of Umicore M73 SIMes (4×238 mg) (Umicore AG &Co. KG, Precious Metals Chemistry, Rodenbacher Chaussee 4, 63457Hanau-Wolfgang, Germany) was added as a slurry in 5 mL PhMe. Each chargewas added at intervals of 40 min. After 4 h, the reaction was cooled to30° C. and di(ethylene glycol) vinyl ether (0.350 mL, 2.56 mmol) wasadded and the solution was stirred overnight with the sparge replacedwith a nitrogen inlet. The reactor was drained and the volume of thereaction was reduced to 1 L. SilaMetS Thiol (70 g) (SiliCycle Inc. 2500,Parc-Technologique Blvd Quebec City, Quebec, Canada) was added and themixture was stirred overnight. The mixture was filtered and the SilaMetSThiol was washed with EtOAc and the filtrate was concentrated.Purification by flash column chromatography on silica gel (330 g GoldRf, eluted with 0% to 100% EtOAc in heptane) gave(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-ylacetate (19.76 g, 28.8 mmol, 90% yield) as an orange oil. MS (ESI, +veion) m/z 685.0 (M+H)⁺.

Step 6:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Sodium methoxide (25% solution in methanol, 11.35 mL, 49.7 mmol) wasadded to a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-ylacetate (19.76 g, 24.83 mmol) in toluene (100 mL) and methanol (20.00mL) at room temperature. After 45 min, the reaction was quenched withcitric acid (2 M aqueous solution, 37.2 mL, 74.5 mmol) and diluted withEtOAc and water. The layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic extracts were washed with 2×water, saturated aqueous sodium chloride, and dried over sodium sulfate.The mixture was filtered and concentrated in vacuo and dried overnightto give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as an orange oil. MS (ESI, +ve ion) m/z 643.0 (M+H)⁺.

Step 7:(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide

To a 1 L flask containing(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (19.1 g, 29.7 mmol), prepared in the previous step, wasadded DCM (300 mL). The solution was cooled in an ice bath for 20 min.Dess-Martin periodinane (15.11 g, 35.6 mmol) was added in one portionand the reaction was stirred while cooled in the ice bath for 40 min.The reaction was removed from the ice bath and stirred for 1.5 h at roomtemperature. Sodium thiosulfate was added followed by water and themixture was stirred vigorously for 20 min. The reaction was diluted withsaturated aqueous sodium bicarbonate and extracted with EtOAc (3×). Thecombined organic layers were washed with water and brine, dried withsodium sulfate, filtered, and concentrated. Purification by silica gelchromatography (eluted with 0% to 60% EtOAc in heptane) gave(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (14.29 g, 22.3 mmol, 75% yield) as a light yellow solid.MS (ESI, +ve ion) m/z 640.8 (M+H)⁺.

Step 8:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 100 mL round-bottomed flask was added 1,3-dithiane (2.025 g, 16.84mmol) in THF (42.1 mL). At −78° C., n-butyllithium (2.5 M solution inhexane, 5.90 mL, 14.7 mmol) was added to the solution. The solution wasstirred for 15 min and then(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (2.70 g, 4.21 mmol) in 10 mL of THF was added slowly.The mixture was stirred for 1 h and 10 mL of saturated ammonium chloridewas added to quench the reaction. The mixture was diluted with 1 N HCl(20 mL) and extracted with EtOAc (3×40 mL). The organic extracts werewashed with saturated NaCl (40 mL) and dried over MgSO₄. The solutionwas filtered and concentrated in vacuo. The material was purified bychromatography through a Redi-Sep pre-packed silica gel column (80 g),eluting with a gradient of 0% to 60% EtOAc (with 0.1% HOAc) in heptaneto give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (1.6 g, 2.1 mmol, 50% yield). MS (ESI, +ve ion) m/z761.1 (M+H)⁺.

Step 9:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 100 mL round-bottomed flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (1.6 g, 2.1 mmol) and iodomethane (1.044 mL, 16.81 mmol)in THF (21 mL). At 0° C., sodium hydride (0.504 g, 21.0 mmol) was addedportion wise. The reaction was stirred at room temperature for 5 h. Thereaction mixture was diluted with saturated NH₄Cl (20 mL) and extractedwith EtOAc (2×20 mL). The combined organic extracts were washed withsaturated NaCl (15 mL) and dried over MgSO₄. The solution was filteredand concentrated in vacuo. Purification by chromatography through aRedi-Sep pre-packed silica gel column (40 g), eluting with a gradient of0% to 60% EtOAc (with 0.1% HOAc) in heptane gave(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.93 g, 1.2 mmol, 57% yield) as an off-white solid. MS(ESI, +ve ion) m/z 775.1 (M+H)⁺.

Step 10:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

To a resealable vial was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.93 g, 1.2 mmol), acetonitrile (9.6 mL) and water (2.4mL). To the mixture was added calcium carbonate (0.600 g, 6.00 mmol) andiodomethane (0.745 mL, 12.0 mmol). The mixture was heated at 45° C.overnight. The solution was poured into saturated NH₄Cl and water andthen extracted with EtOAc. The combined extracts were washed with brineand then dried over Na₂SO₄ and concentrated. Purification by silica gelchromatography (eluted with 0% to 60% EtOAc in heptane (with 0.1% AcOH)gave(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.70 g, 1.021 mmol, 85% yield) as a white solid. MS(ESI, +ve ion) m/z 685.1 (M+H)⁺.

Step 11:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 100 mL round-bottomed flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (450 mg, 0.657 mmol),(S)-octahydropyrazino[2,1-c][1,4]oxazine HCl salt (1130 mg, 5.25 mmol)and N,N-diisopropylethylamine (2.341 mL, 13.13 mmol) in DCM (13.1 mL).Titanium(IV) isopropoxide (0.770 mL, 2.63 mmol) was added to thesolution slowly. The reaction was stirred at room temperature overnight.Sodium triacetoxyborohydride (278 mg, 1.31 mmol) was added to thereaction portion wise and the mixture was stirred overnight. Thereaction was diluted with saturated NaCl (20 mL). The white precipitatewas removed by filtration through Celite. The filtrate was concentratedand diluted with 1 N HCl (20 mL) and extracted with EtOAc (3×50 mL). Thecombined organic extracts were washed with saturated NaCl (50 mL) anddried over MgSO₄. The solution was filtered and concentrated in vacuo.The concentrate was absorbed onto a plug of silica gel and purified bychromatography through a Redi-Sep pre-packed silica gel column (40 g,with a layer of sodium bicarbonate on top). Elution with a gradient of0% to 10% methanol in DCM gave(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (420 mg, 0.518 mmol, 79% yield) as a white solid. MS(ESI, +ve ion) m/z 811.0 (M+H)⁺. 1H NMR (400 MHz, dichloromethane-d₂) δppm 0.91-1.10 (m, 3H), 1.33-1.72 (m, 10H, with water residue), 1.81-1.97(m, 5H), 2.03-2.39 (m, 10H), 2.41-2.69 (m, 6H), 2.71-2.83 (m, 2H),2.90-3.08 (m, 2H), 3.12-3.27 (m, 2H), 3.33 (s, 3H), 3.37 (s, 3H),3.53-3.83 (m, 6H), 3.95-4.09 (m, 3H), 4.11-4.22 (m, 1H), 5.23-5.29 (m,1H), 5.55-5.62 (m, 1H), 6.80-6.93 (m, 2H), 7.09 (s, 1H), 7.13-7.22 (m,1H), 7.30 (s, 1H), 7.72 (d, J=8.41 Hz, 1H).

Example 12(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 25 mL flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (80 mg, 0.117 mmol), (R)-1-isopropyl-2-methylpiperazinebis(2,2,2-trifluoroacetate) (330 mg, 0.891 mmol),N,N-diisopropylethylamine (366 μL, 2.10 mmol) and titanium(IV)isopropoxide (137 μL, 0.467 mmol) in DCM (2335 μL). The solution wasstirred at room temperature overnight. To this solution was added sodiumtriacetoxyborohydride (99 mg, 0.47 mmol). The reaction was stirred for24 h. The reaction mixture was diluted with 1 N HCl (10 mL) andextracted with DCM (2×20 mL). The organic solvent was concentrated. Theresidue was purified by prep-HPLC to give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 811.2 (M+H)⁺. ¹HNMR (400 MHz, MeOH-d₄) δ ppm 1.06 (d, J=6.06 Hz, 3H), 1.25-1.48 (m,10H), 1.49-2.30 (m, 12H), 2.42-2.84 (m, 8H), 2.94-3.27 (m, 4H), 3.35 (s,3H), 3.42 (s, 4H), 3.51-3.74 (m, 5H), 3.91-4.10 (m, 3H), 4.14-4.25 (m,1H), 5.35 (d, J=16.04 Hz, 1H), 5.69-5.82 (m, 1H), 6.86-6.94 (m, 1H),7.01 (dd, J=8.02, 1.76 Hz, 1H), 7.10 (d, J=1.96 Hz, 1H), 7.16 (dd,J=8.41, 2.15 Hz, 1H), 7.26 (d, J=1.37 Hz, 1H), 7.73 (d, J=8.61 Hz, 1H).

Example 13(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 100 mL round-bottomed flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.62 g, 0.814 mmol) and iodoethane (0.655 mL, 8.14mmol) in N, N-dimethylformamide (8.14 mL). At 0° C., potassiumbis(trimethylsilyl)amide (1 M in THF, 8.14 mL, 8.14 mmol) was addedslowly. The reaction was stirred overnight. The reaction mixture wasdiluted with 1 N HCl (15 mL) and extracted with EtOAc (3×15 mL). Theorganic extract was washed with saturated NaCl (15 mL) and dried overMgSO₄. The solution was filtered and concentrated in vacuo. Theconcentrate was absorbed onto a plug of silica gel and purified bychromatography through a 24 g ISCO gold column, eluted with a gradientof 0% to 40% EtOAc (with 0.1% of HOAc) in heptane, to provide(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.24 g, 0.304 mmol, 37% yield). MS (ESI, +ve ion) m/z789.1 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

To a resealable vial was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (510 mg, 0.646 mmol), acetonitrile (5168 μL) and water(1292 μL). To the mixture was added calcium carbonate (323 mg, 3.23mmol) and iodomethane (401 μL, 6.46 mmol). The mixture was heated at 45°C. overnight. The reaction was diluted with saturated NH₄Cl (10 mL) andextracted with EtOAc (3×15 mL). The combined organic extracts werewashed with saturated NaCl (20 mL) and dried over MgSO₄. The solutionwas filtered and concentrated in vacuo. The concentrate was absorbedonto a plug of silica gel and purified by chromatography through aRedi-Sep pre-packed silica gel column (40 g), eluting with a gradient of0% to 60% EtOAc (with 0.1% of HOAc), to provide(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (230 mg, 0.329 mmol, 50.9%yield) as a white solid. MS (ESI, +ve ion) m/z 699.1 (M+H)⁺.

Step 3:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-1′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 50-mL round-bottomed flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (150 mg, 0.215 mmol),(S)-octahydropyrazino[2,1-c][1,4]oxazine HCl salt (277 mg, 1.29 mmol)and N,N-diisopropylethylamine (574 μL, 3.22 mmol) in DCM (4290 μL). Thereaction was stirred at room temperature overnight. Sodiumtriacetoxyborohydride (182 mg, 0.858 mmol) was added to the reactionmixture. The reaction was stirred for 8 h. The reaction mixture wasdiluted with 1 N HCl (20 mL) and extracted with DCM (2×20 mL). Theorganic layer was fully concentrated. The residue was further purifiedby prep-HPLC. The solution after pre-HPLC was washed with pH 7 solutionand extracted with EtOAc (2×20 mL). The organic extract was washed withsaturated NaCl (20 mL) and dried over MgSO₄. The solution was filteredand concentrated in vacuo to give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 825.2 (M+H)⁺. ¹HNMR (400 MHz, dichloromethane-d₂) δ ppm 1.01 (d, J=6.26 Hz, 3H), 1.35(t, J=6.85 Hz, 3H), 1.44-1.74 (m, 7H), 1.77-2.01 (m, 5H), 2.04-2.38 (m,9H), 2.41-2.65 (m, 5H), 2.70-2.83 (m, 2H), 2.86-3.08 (m, 2H), 3.27 (d,J=14.28 Hz, 1H), 3.35 (s, 3H), 3.40-3.49 (m, 1H), 3.52-3.83 (m, 7H),3.99-4.10 (m, 3H), 4.12-4.28 (m, 1H), 5.35-5.42 (m, 1H), 5.57-5.76 (m,1H), 6.85-6.92 (m, 2H), 7.09 (d, J=2.15 Hz, 1H), 7.13-7.20 (m, 1H), 7.24(s, 1H), 7.72 (d, J=8.41 Hz, 1H).

Example 14(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 25 mL flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (130 mg, 0.186 mmol) in DCM (3718 μL). To this solutionwas added 1-(oxetan-3-yl)piperazine (159 mg, 1.12 mmol) and a drop ofacetic acid. The mixture was stirred for 8 h and sodiumtriacetoxyborohydride (158 mg, 0.744 mmol) was added. The reaction wasstirred for 2 h and diluted with 1 N HCl (10 mL) and extracted with DCM(3×15 mL). The organic layer was concentrated. The concentrate waspurified by prep-HPLC. The solution from prep-HPLC was washed with pH 7buffer and extracted with EtOAc. The organic layer was concentrated togive(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 825.2 (M+H)⁺. ¹HNMR (400 MHz, dichloromethane-d₂) δ ppm 0.98 (br s, 3H), 1.29-1.43 (m,4H), 1.47-2.24 (m, 12H), 2.24-2.41 (m, 4H), 2.45-2.84 (m, 9H), 2.87-3.07(m, 1H), 3.27 (br d, J=14.09 Hz, 1H), 3.34 (s, 3H), 3.39-3.52 (m, 2H),3.57-3.76 (m, 4H), 3.95-4.20 (m, 4H), 4.45-4.55 (m, 2H), 4.57-4.65 (m,2H), 5.38-5.51 (m, 1H), 5.59-5.74 (m, 1H), 6.89 (s, 2H), 7.09 (d, J=1.96Hz, 1H), 7.13-7.19 (m, 1H), 7.21-7.28 (m, 1H), 7.72 (d, J=8.41 Hz, 1H).

Example 15(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 25 mL flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (60 mg, 0.086 mmol) and(9ar)-octahydro-2h-pyrido[1,2-a]pyrazine (120 mg, 0.858 mmol) in DCM(1716 μL). A drop of acetic acid was added. The solution was stirred atroom temperature overnight. To this solution was added sodiumtriacetoxyborohydride (73 mg, 0.34 mmol). The reaction was stirred for 8h and diluted with 1 N HCl (10 mL) and extracted with DCM (2×10 mL). Thesolvent was removed under reduced pressure. The concentrate was purifiedby prep-HPLC to give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 823.2 (M+H)⁺. ¹HNMR (400 MHz, MeOH-d₄) δ ppm 1.05 (d, J=6.46 Hz, 3H), 1.37 (t, J=6.85Hz, 3H), 1.41-2.02 (m, 14H), 2.04-2.26 (m, 5H), 2.30-2.51 (m, 2H),2.51-2.87 (m, 6H), 2.92-3.08 (m, 3H), 3.11-3.26 (m, 2H), 3.35-3.54 (m,7H), 3.60-3.78 (m, 4H), 3.94-4.11 (m, 3H), 4.18-4.29 (m, 1H), 5.43 (d,J=16.04 Hz, 1H), 5.67-5.89 (m, 1H), 6.87-6.94 (m, 1H), 6.95-7.03 (m,1H), 7.10 (d, J=1.96 Hz, 1H), 7.14-7.19 (m, 1H), 7.24 (d, J=1.56 Hz,1H), 7.73 (d, J=8.61 Hz, 1H).

Example 16(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 10 mL flask was added 1-isopropylpiperazine (123 μL, 0.858 mmol)and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (60 mg, 0.086 mmol) in DCM (1716 μL). A drop of aceticacid was added and the reaction was stirred overnight. Sodiumtriacetoxyborohydride (72.7 mg, 0.343 mmol) was added to the reactionmixture. The reaction was stirred at room temperature for 8 h. Thereaction mixture was diluted with 1 N HCl (5 mL) and extracted with DCM(2×10 mL). The organic layer was concentrated. The concentrate waspurified by prep-HPLC to give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 811.2 (M+H)⁺. ¹HNMR (400 MHz, MeOH-d₄) δ ppm 1.05 (d, J=6.46 Hz, 3H), 1.29-1.47 (m,10H), 1.52-2.30 (m, 12H), 2.51-2.87 (m, 8H), 2.93-3.11 (m, 2H), 3.38 (s,4H), 3.45-3.57 (m, 3H), 3.59-3.78 (m, 4H), 3.95-4.11 (m, 3H), 4.20-4.33(m, 1H), 5.45 (d, J=15.85 Hz, 1H), 5.77-5.91 (m, 1H), 6.84-6.94 (m, 1H),6.96-7.02 (m, 1H), 7.10 (d, J=1.96 Hz, 1H), 7.16 (br d, J=8.41 Hz, 1H),7.23 (d, J=1.57 Hz, 1H), 7.73 (d, J=8.41 Hz, 1H).

Example 17(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 25 mL flask was added(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (80 mg, 0.11 mmol), (R)-1-isopropyl-2-methylpiperazinebis(2,2,2-trifluoroacetate) (254 mg, 0.686 mmol),N,N-diisopropylethylamine (408 μL, 2.29 mmol) and titanium(IV)isopropoxide (134 L, 0.458 mmol) in DCM (2288 μL). The solution wasstirred at room temperature for 8 h. To this solution was added sodiumtriacetoxyborohydride (97 mg, 0.46 mmol). The reaction was stirredovernight. The reaction mixture was diluted with 1 N HCl (10 mL) andextracted with DCM (2×10 mL). The solvent was concentrated. The residuewas purified by prep-HPLC to give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 825.4 (M+H)⁺. ¹HNMR (400 MHz, MeOH-d₄) δ ppm 1.05 (d, J=6.46 Hz, 3H), 1.21-1.49 (m,13H), 1.51-2.28 (m, 12H), 2.37-2.87 (m, 8H), 2.92-3.20 (m, 3H),3.36-3.57 (m, 7H), 3.60-3.79 (m, 4H), 3.97-4.07 (m, 3H) 4.20-4.31 (m,1H), 5.43 (d, J=16.04 Hz, 1H), 5.75-5.90 (m, 1H), 6.87-6.94 (m, 1H),6.98-7.01 (m, 1H), 7.10 (d, J=1.37 Hz, 1H), 7.14-7.19 (m, 1H), 7.24 (d,J=1.37 Hz, 1H), 7.73 (d, J=8.61 Hz, 1H).

Example 18(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(S,E)-(6-chloro-1-((hydroxyimino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate

To a stirred solution of(R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate (425 g, 1042 mmol) in DCM (5100 mL) and MeOH (5100 mL)under a nitrogen atmosphere was added pyridine (337 mL, 4170 mmol)followed by hydroxylamine hydrochloride (145 g, 2085 mmol). The reactionmixture was stirred at room temperature for 3 h. The reaction wasdiluted with DCM (2.0 L) and the organic layer was washed with water(2.0 L). The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure to yield(S,E)-(6-chloro-1-((hydroxyimino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate as yellow liquid. The material was used in the next stepwithout further purification. ¹H NMR (400 MHz, Chloroform-d) δ 7.85-7.80(dd, J=8.7, 2.1 Hz, 2H), 7.58-7.55 (m, 2H), 7.51 (s, 1H), 7.23-7.26 (m,1H), 7.14-7.16 (m, 2H), 4.66-4.64 (d, J=11.3 Hz, 1H), 4.56-4.53 (d,J=11.2 Hz, 1H), 2.84-2.81 (t, J=6.3 Hz, 2H), 2.14-2.02 (dddd, J=14.8,13.2, 7.1, 3.8 Hz, 2H), 1.96-1.83 (dddt, J=13.9, 11.8, 5.9, 3.7 Hz, 2H).

Step 2:(S)-(1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methanolhydrochloride

(S,E)-(6-Chloro-1-((hydroxyimino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate (425 g, 1005 mmol), prepared in the previous step, wasdissolved in THF (5160 mL) under a nitrogen atmosphere. The reactionmixture was cooled to 0° C. and lithium aluminum hydride (1.0 M in THF,3519 mL, 3519 mmol) was added drop-wise. The ice-bath was removed andthe reaction mixture was stirred at room temperature for 3 h. Thereaction was cooled to 0° C. and water (160 mL) was added slowly,followed by 15% aqueous NaOH solution (160 mL) and water (500 mL). Themixture was allowed to stir for 10 min at room temperature and thereaction was filtered. The residual solids were washed with hot ethylacetate (3×4.0 L). The combined filtrate was concentrated under reducedpressure to yield a yellow oil. The residue was dissolved in DCM (5160mL) and the solution was cooled to 0° C. A solution of HCl (4.0 M indioxane, 65 mL) was added drop-wise and mixture was allowed to stir for15 min at room temperature. The precipitate was collected by filtration.The solid was washed with ice-cold DCM (100 mL) and dried to afford(S)-(1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methanolhydrochloride (192 g, 72.8% yield). ¹H NMR (400 MHz, Methanol-d₄) δ7.38-7.36 (d, J=8.2 Hz, 1H), 7.23-7.20 (m, 2H), 3.81-3.78 (m, 1H),3.69-3.68 (dd, J=10.9, 1.3 Hz, 1H), 3.48-3.45 (d, J=13.1 Hz, 1H),3.23-3.20 (d, J=13.2 Hz, 1H), 2.83-2.81 (d, J=6.3 Hz, 2H), 2.17-2.11 (m,1H), 1.91-1.85 (m, 2H), 1.83-1.74 (m, 1H); exchangeable protons notobserved.

Step 3: (S)-methyl5-((1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate

To a stirred solution of(S)-(1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methanolhydrochloride (150 g, 572 mmol) was dissolved in dry DMSO (2250 mL)under a nitrogen atmosphere at room temperature. The solution wastreated with 6-bromo-5-fluoropicolinic acid (151 g, 687 mmol) and theresulting solution was treated with potassium 2-methylpropan-2-olate(218 g, 1945 mmol) at room temperature. The reaction mixture was stirredfor 2 h at room temperature and quenched by addition of acetic acid(˜170 mL) at room temperature, followed by water (1.5 L) which resultedin precipitation of a solid. The solid was collected by filtration,washed with water (1.0 L), and dried. The solid was added to a pre-mixedsolution of MeOH/H₂SO₄ (10:1, v/v, 5400 mL) and stirred at 80° C. for 3h. The mixture was cooled to room temperature and solid K₂CO₃ (600 g)was slowly added to quench the sulfuric acid. The mixture was suspendedin water (2 L) and ethyl acetate (2 L). The layers were separated. Theaqueous layer was extracted with ethyl acetate (2×2.5 L). The combinedorganic extracts were washed with brine (2.0 L), dried over Na₂SO₄, andfiltered. The filtrate was concentrated under reduced pressure.Purification by column chromatography on silica gel (60-120 mesh, elutedwith 0% to 5% MeOH in DCM) gave (S)-methyl5-((1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate(170 g, 67.6% yield) as off-white solid. MS (ESI, +ve ion) m/z 439.0(M+1). ¹H NMR (400 MHz, Chloroform-d) δ 8.06-8.04 (dd, J=8.4, 1.0 Hz,1H), 7.51-7.49 (d, J=8.4 Hz, 1H), 7.18-7.14 (m, 3H), 4.18-4.11 (m, 2H),3.93 (s, 3H), 3.25-3.17 (m, 2H), 2.80-2.76 (m, 2H), 2.06-1.97 (m, 2H),1.94-1.85 (tdd, J=9.5, 6.7, 4.2 Hz, 2H); exchangeable protons notobserved.

Step 4: methyl5-(((S)-1-(((((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)amino)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate

To a stirred solution of (S)-methyl5-((1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate(170 g, 387 mmol) in dry DCM (1.7 L) and acetic acid (1105 mL) under anitrogen atmosphere was added((1R,2S)-2-((S)-(1H-benzo[d][1,2,3]triazol-1-yl)(hydroxy)methyl)cyclobutyl)methylacetate (128 g, 464 mmol) followed by sodium cyanoborohydride (31.6 g,503 mmol) at 0° C. The reaction was maintained at 0° C. for 2 h. Thereaction was poured slowly into cold 10% sodium bicarbonate solution.The aqueous phase was extracted with ethyl acetate (2×2.0 L). Thecombined organic layer was washed with brine (1.0 L) and dried oversodium sulfate and concentrated under reduced pressure. Purification bycolumn chromatography on silica gel (60-120 mesh, eluted with 2% to 5%MeOH in DCM) gave methyl5-(((S)-1-(((((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)amino)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate(149 g, 66.5% yield) as yellow liquid. MS (ESI, +ve ion) m/z 579.1(M+1). ¹H NMR (400 MHz, Chloroform-d) δ 8.08-8.06 (dt, J=8.4, 1.3 Hz,1H), 7.55-7.53 (dd, J=8.3, 1.6 Hz, 1H), 7.19-7.13 (m, 3H), 4.13 (s, 2H),4.10-4.00 (t, J=2.3 Hz, 2H), 3.98 (d, J=1.4 Hz, 3H), 3.05-2.98 (m, 2H),2.79-2.78 (m, 2H), 2.69-2.58 (m, 2H), 2.18-2.11 (dd, J=8.9, 4.9 Hz, 2H),2.09-2.06 (dq, J=9.7, 4.8, 3.1 Hz, 1H), 2.00 (t, J=1.3 Hz, 3H),1.97-1.82 (m, 6H), 1.65-1.61 (d, J=9.2 Hz, 1H), 1.59-1.51 (q, J=8.9 Hz,1H).

Step 5: (S)-methyl5′-(((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)-6-chloro-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate

A solution of methyl5-(((S)-1-(((((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)amino)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate(36 g, 62.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (161 mL, 933mmol) in N-methyl-2-pyrrolidinone (360 mL) was stirred at 130° C. undera nitrogen atmosphere for 16 h. The reaction was cooled to roomtemperature and diluted with ethyl acetate (1.0 L). The mixture waswashed with water (5×400 mL). The organic layer was dried with sodiumsulfate, filtered, and concentrated under reduced pressure. Purificationby column chromatography on silica gel (60-120 mesh, 0% to 10% EtOAc inhexane) gave (S)-methyl5′-(((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)-6-chloro-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate(16 g, 51.7% yield) as yellow liquid. MS (ESI, +ve ion) m/z 499.1 (M+1).¹H NMR (400 MHz, Chloroform-d) δ 7.72-7.70 (d, J=8.5 Hz, 1H), 7.46-7.44(dd, J=7.9, 1.1 Hz, 1H), 7.21-7.20 (dd, J=8.5, 2.2 Hz, 1H), 7.18-7.11(m, 2H), 4.18-4.15 (d, J=12.2 Hz, 1H), 4.05-3.98 (m, 3H), 3.95-3.93 (d,J=4.5 Hz, 1H), 3.91-3.89 (d, J=1.0 Hz, 3H), 3.74-3.70 (d, J=14.5 Hz,1H), 3.42-3.32 (m, 2H), 2.79-2.76 (dt, J=9.0, 5.1 Hz, 2H), 2.55-2.49(dt, J=15.5, 7.4 Hz, 2H), 1.98-1.85 (m, 8H), 1.76-1.74 (t, J=9.4 Hz,1H), 1.62-1.61 (d, J=1.1 Hz, 1H), 1.50-1.49 (d, J=1.1 Hz, 1H).

Step 6: (S)-methyl6-chloro-5′-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate

To a stirred solution of (S)-methyl5′-(((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)-6-chloro-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate(68 g, 136 mmol) in THF (680 mL) and water (680 mL) was added lithiumhydroxide monohydrate (22.87 g, 545 mmol) at room temperature. Thereaction was allowed to stir at room temperature for 12 h. The reactionwas concentrated under reduced pressure and the residue was taken up inMTBE (1.0 L), 10% citric acid monohydrate solution (500 mL) was addedand the solution was stirred for 10 min. The layers were separated andthe organic layer was washed with brine (500 mL), dried over sodiumsulfate, and concentrated under reduced pressure. The concentrate wasdissolved in dry methanol (600 mL) and cooled to 0° C. Thionyl chloride(14.92 mL, 204 mmol) was added and the reaction was heated at 60° C. for12 h. The reaction was cooled to 0° C. and quenched by slow addition of10% sodium bicarbonate solution (500 mL) and extracted with ethylacetate (2×500 mL). The combined organic layer was washed with brine(300 mL), dried over sodium sulfate, and concentrated under reducedpressure. The concentrate was suspended in acetonitrile (140 mL) andwater (140 mL) was added. The mixture was stirred for 10 min. The solidwas collected by filtration and dried to give (S)-methyl6-chloro-5′-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate(58 g, 93% yield). MS (ESI, +ve ion) m/z 457.1 (M+1). ¹H NMR (400 MHz,Chloroform-d) δ 7.73-7.72 (d, J=8.5 Hz, 1H), 7.47-7.45 (d, J=7.9 Hz,1H), 7.21-7.19 (dd, J=8.5, 2.3 Hz, 1H), 7.14-7.11 (m, 2H), 4.44-4.40 (m,1H), 4.16-4.13 (d, J=12.1 Hz, 1H), 4.06-4.03 (d, J=12.1 Hz, 1H), 3.95(s, 3H), 3.84-3.80 (d, J=14.4 Hz, 1H), 3.75-3.68 (m, 1H), 3.57-3.56(ddt, J=14.1, 9.3, 4.2 Hz, 2H), 3.37-3.36 (d, J=14.5 Hz, 1H), 2.96-2.90(dd, J=14.0, 9.1 Hz, 1H), 2.82-2.76 (m, 2H), 2.58-2.54 (m, 1H), 2.32(td, J=12.2, 10.4, 6.3 Hz, 1H), 2.02-1.95 (m, 3H), 1.88-1.83 (m, 2H),1.67-1.55 (m, 2H), 1.49-1.43 (m, 1H).

Step 7: (S)-methyl6-chloro-5′-(((1R,2R)-2-formylcyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate

A 1 L 3-neck flask equipped with a mechanical stir bar and a temperatureprobe was charged with DCM (220 mL, 5V) followed by oxalyl chloride(10.16 mL, 116 mmol). The solution was cooled to −73° C. in a dry-iceacetone bath. DMSO (17.15 mL, 242 mmol) was added via syringe over 7 min(internal temperature increased from −74° C. to −60° C. during theaddition). The mixture was held for 14 min and a solution of (S)-methyl6-chloro-5′-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate(44.2 g, 97 mmol) in DCM (220 mL, 5V) cooled in a dry-ice acetone bathwas added via cannula over 12 min (internal temperature increased from−75° C. to −72° C. during the addition). The solution was stirred for 17min and triethylamine (67.4 mL, 484 mmol) was added over 7 min (internaltemperature increased from −76° C. to −65° C. during the addition).After the addition of the Et₃N, the reaction was held in the dry iceacetone bath for 5 min then warmed to 7° C. over 4 h and quenched withwater (220 mL, 5V) (internal temperature increased from 7° C. to 15° C.during the quench). The mixture was transferred to a separatory funneland the aqueous layer was discarded. The bottom layer was washed withsaturated NH₄Cl (220 mL, 5V), 1:1 water:saturated NaHCO₃(220 mL, 5V),and 1:1 water:brine (220 mL, 5V). The bottom organic layer was driedover MgSO₄, filtered through a fine frit, and concentrated under reducedpressure to give an off white foam. The foam was dissolved in 1:1EtOAc/DCM (100 mL) and filtered through a 2 cm pad of silica (elutedwith 400 mL of 1:1 EtOAc/DCM). The solution was concentrated underreduced pressure, diluted with PhMe (100 mL) and concentrated. This wasrepeated twice more and the product (S)-methyl6-chloro-5′-(((1R,2R)-2-formylcyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylatewas used without further purification. MS (ESI, +ve ion) m/z 454.9(M+H)⁺.

Step 8: (1S)-methyl6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate

To a 2 L jacketed reactor was charged (−)-cinchonidine (5.69 g, 19.34mmol) followed by PhMe (220 mL, 5V) and THF (220 mL, 5V). The solutionwas cooled to −23° C. (internal temperature) and zinc chloride (1.9 M in2-methyltetrahydrofuran, 81 mL, 155 mmol) was added over 3 min (internaltemperature increased from −23° C. to −19° C. during the addition). Thesolution was stirred for 5 min and vinylmagnesium chloride (1.6 Msolution in THF, 206 mL, 329 mmol) was added via an addition funnel over24 min (internal temperature increased from −21° C. to −13° C. duringthe addition). The solution was stirred for 20 min (internal temperaturedecreased to −22° C.) and a solution of (S)-methyl6-chloro-5′-(((1R,2R)-2-formylcyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate,prepared in the previous step, in PhMe (220 mL, 5V) cooled in anice-water bath was added via cannula over 8 min (internal temperatureincreased from −22° C. to −16° C. during the addition). The reaction wasstirred at −20° C. for 1 h and warmed to 0° C. After 45 min, thereaction was cooled to −8° C. and quenched with saturated NH₄Cl (350 mL,8V). Water (88 mL, 2V) was added. Ammonium hydroxide (20 mL, 0.45V) wasadded and the solids dissolved. The aqueous phase was discarded. Theorganic phase was washed with saturated NH₄Cl (220 mL, 5 V), 1 M citricacid (4×88 mL, 2V), 1:1 water:brine (440 mL, 10V), dried over MgSO₄,filtered, and concentrated to give a yellow oil. MeOH (200 mL) was addedand removed under reduced pressure. This was repeated a second time andthe product (1S)-methyl6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylatewas used without further purification as a mixture of diastereomers. MS(ESI, +ve ion) m/z 483.0 (M+H)⁺.

Step 9:(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylicacid

To a 2 L jacketed reactor was charged a solution of (1S)-methyl6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate,prepared in the previous step, in MeOH (234 mL, 5V) and THF (234 mL,5V). Lithium hydroxide monohydrate (16.23 g, 387 mmol) was added and thereaction was stirred at room temperature for 17 h. Citric acid (1 M inwater, 180 mL) was added followed by water (187 mL, 4V) and EtOAc (234mL, 5V). All the solids dissolved. The mixture was drained from thereactor into a 3 L flask and the mixture was concentrated to half theoriginal volume. EtOAc (234 mL, 5V) was added and the mixture wastransferred to a separatory funnel. The pH of the aqueous layer was 5.The aqueous layer was discarded. The organic layer was washed with 1:1water:brine (235 mL, 5V), dried over MgSO₄, filtered, and concentratedto give 47.0 g of a yellow solid that was 79 wt %(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylicacid (37.1 g, 79 mmol, 82% yield) and a mixture of diastereomers. MS(ESI, +ve ion) m/z 469.0 (M+H)⁺.

Step 10:(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide

To a mixture of(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylicacid (34.7 g, 58.5 mmol), 4-(dimethylamino)pyridine (21.42 g, 175 mmol),and (2R,3S)-3-methylhex-5-ene-2-sulfonamide (21.41 g, 117 mmol) in a 500mL 1-neck flask was added PhMe (100 mL). The PhMe was removed underreduced pressure and the concentrate was diluted with DCM (347 mL, 10V)and transferred to a 3-neck 1 L flask equipped with a temperature probeand a magnetic stirrer. Triethylamine (24.44 mL, 175 mmol) and1-β-dimethylaminopropyl)-3-ethylcarbodiimide HCl (22.41 g, 117 mmol)were added and the reaction was stirred at room temperature. After 43 h,the reaction was diluted with water (240 mL, 7V) and transferred to aseparatory funnel. The pH of the aqueous phase was adjusted to 4 with 1M citric acid (240 mL, 7V) and the aqueous phase was discarded. Theorganic phase was washed with 1:1 brine:water (240 mL, 7V), dried overMgSO₄, filtered, and concentrated. Purification by flash columnchromatography on silica gel (330 g silica, eluted with 50% to 100% DCMin heptane) gave(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide(24.7 g, 39.3 mmol, 67% yield) as a pale yellow foam and a mixture ofdiastereomers. MS (ESI, +ve ion) m/z 628.0 (M+H)⁺.

Step 11:(S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide

A solution of(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide(2.82 g, 4.49 mmol) in DCM (28 mL, 10V) in a 100 mL 1-neck flaskequipped with a temperature probe and magnetic stir bar was cooled to 2°C. in an ice-water bath and Dess-Martin periodinane (2.094 g, 4.94 mmol)was added in one portion. The reaction was warmed to room temperatureover 20 min and stirred at room temperature for 30 min. The solution wascooled to 2° C. in a water-ice bath and quenched with a solution ofsodium thiosulfate (2.4 g) in water (8.4 mL, 3V) followed by saturatedNaHCO₃(20 mL, 7V). The internal temperature increased from 2° C. to 7°C. during the quench. The reaction was removed from the water-ice bath,warmed to room temperature, and stirred for 30 min. The mixture wastransferred to a separatory funnel. The pH was adjusted to 7 with 1 Mcitric acid. The aqueous layer was discarded. The organic phase waswashed with 1:1 water:brine (28 mL, 10V), dried over MgSO₄, filtered,and concentrated to give a yellow foam. The concentrate was dissolved in10% EtOAc in DCM (˜50 mL) and filtered through a 1 cm pad of silica gel(eluted with ˜100 mL of 10% EtOAc in DCM). The filtrate was concentratedto give(S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((2R,3S)-3-methyl)-6-chloro-N-)-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamideas a pale yellow foam that was used without further purification. MS(ESI, +ve ion) m/z 625.8 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.14 (d, J=6.85 Hz, 3H), 1.45 (d, J=7.04 Hz, 3H), 1.48-1.56 (m, 1H),1.81-2.05 (m, 6H), 2.10-2.19 (m, 2H), 2.27 (q, J=8.80 Hz, 1H), 2.62 (qd,J=7.14, 2.45 Hz, 1H), 2.73-2.87 (m, 2H), 3.04-3.17 (m, 1H), 3.30 (q,J=8.80 Hz, 1H), 3.36-3.43 (m, 1H), 3.43-3.47 (m, 1H), 3.78 (d, J=14.48Hz, 1H), 3.89-4.07 (m, 3H), 4.20 (d, J=12.32 Hz, 1H), 5.07-5.15 (m, 2H),5.74-5.87 (m, 2H), 6.15-6.32 (m, 2H), 7.12 (d, J=2.15 Hz, 1H), 7.18-7.22(m, 2H), 7.58 (d, J=7.83 Hz, 1H), 7.69 (d, J=8.41 Hz, 1H), 9.90 (s, 1H).

Step 12:(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide

To a 4-neck flask equipped with a magnetic stir bar, a temperatureprobe, and an air cooled condenser was charged PhMe (1.8 L, 250V). Thesolvent was heated to 80° C. and a gas dispersion tube was immersed intothe solvent. Nitrogen gas was bubbled through the solvent via the gasdispersion tube. A solution of(S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide(8.93 g, 80 wt %, 11.41 mmol) in PhMe (65 mL) was added via an additionfunnel over 2 h. During the addition of the diene, Umicore M73 SIMes(Umicore AG & Co. KG, Precious Metals Chemistry, Rodenbacher Chaussee 4,63457 Hanau-Wolfgang, Germany) was added in four equal portions (totalamount of catalyst was 0.346 g, 0.456 mmol) as a suspension in PhMe (4mL) via syringe at: t=0 min, t=30 min, t=60 min, and t=90 min. After theaddition of the diene was complete, the reaction was stirred for anadditional 1 h at 80° C. The reaction was cooled to room temperature and2-(2-(vinyloxy)ethoxy)ethanol (0.125 mL, 0.913 mmol) and SilaMetS Thiol(SiliCycle Inc. 2500, Parc-Technologique Blvd Quebec City, Quebec,Canada) (7.71 g) were added. The mixture was stirred at room temperaturefor 18 h and the SilaMetS Thiol was removed by filtration and washedwith EtOAc and concentrated to give a tan color solid. MeOH (˜50 mL) wasadded and removed under reduced pressure. MeOH (107 mL, 15V) was addedand the slurry was stirred at room temperature for 3 d and collected byfiltration. The solid was washed with MeOH (1×40 mL) and dried on a fritunder a vacuum with a positive flow of nitrogen to give 6.39 g of an offwhite solid that was 66 wt %(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (4.22 g, 7.0 mmol, 62% yield). MS (ESI, +ve ion) m/z598.1 (M+H)⁺.

Step 13:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 3-neck flask equipped with temperature probe, septum, and nitrogeninlet was charged(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (6.33 g, 66 wt %, 6.98 mmol) and trimethylsulfoniumiodide (2.138 g, 10.48 mmol). DMSO (35 mL) and THF (8.75 mL) were addedand the mixture was stirred at room temperature for 20 min until thesolids dissolved. The solution was cooled in an ice-water bath. When theinternal temperature reached 6.5° C., potassium tert-butoxide (1.0 Msolution in THF, 17.46 mL, 17.46 mmol) was added slowly via syringe.After 40 min, a small amount of trimethylsulfonium iodide was addedfollowed by potassium tert-butoxide (1 M solution in THF, 1.2 mL, 1.2mmol). After 15 minutes, zinc(II) trifluoromethanesulfonate (0.5 M inMeOH, 84 mL, 41.9 mmol) was added over 5 min. After addition, thereaction was warmed to room temperature, stirred for 2 h and quenchedwith saturated ammonium chloride (˜150 mL). Water and EtOAc were added.The aqueous phase was extracted with EtOAc (3×). The combined organicextracts were concentrated. The concentrate was dissolved in EtOAc,washed with water (2×), brine (1×), dried over Na₂SO₄, filtered, andconcentrated. The material was absorbed onto silica gel. Purification byflash column chromatography (330 g silica, eluted with 10% to 80% EtOAc(2% AcOH) in heptane) gave 5.17 g of a light yellow solid that was 57 wt%(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (2.93 g, 4.55 mmol, 65% yield). MS (ESI, +ve ion) m/z644.0 (M+H)⁺.

Step 14:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

To a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (79 wt %, 7.4 g, 9.07 mmol) in DCM (60 mL) and DMSO (30mL) was added N,N-diisopropylethylamine (7.92 mL, 45.4 mmol). Thesolution was cooled in an ice water bath and pyridine-sulfur trioxidecomplex (3.61 g, 22.69 mmol) was added. After 40 min, the reaction wasquench with saturated ammonium chloride and diluted water and EtOAc. Theorganic phase was washed with water. The combined aqueous phase wasextracted with EtOAc (2×). The combined organic phase was washed with50% saturated ammonium chloride (2×), brine, dried over Na₂SO₄,filtered, and concentrated to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide which was used without further purification. MS (ESI,+ve ion) m/z 641.9 (M+H)⁺.

Step 15:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (5.28 g, 8.22 mmol) and(S)-octahydropyrazino[2,1-c][1,4]oxazine (3.51 g, 24.67 mmol) in DCM (82mL) at room temperature was added acetic acid (0.475 mL, 8.22 mmol). Themixture was stirred at room temperature for 1 h and sodiumtriacetoxyborohydride (2.091 g, 9.87 mmol) was added slowly over 1 min.After 1 h, additional sodium triacetoxyborohydride (300 mg) was added.The reaction was stirred for 30 min and quenched with saturated NH₄Cl.The aqueous phase was extracted with DCM (3×). The combined organicextracts were washed with saturated NH₄Cl (1×), brine (1×), dried overNa₂SO₄, filtered, and concentrated. Purification by flash columnchromatography (330 g silica, eluted with 0% to 10% MeOH in DCM) gave(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (6.02 g, 7.83 mmol, 95% yield) as off-white solid. MS(ESI, +ve ion) m/z 768.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.17 (d, J=6.85 Hz, 3H), 1.46 (d, J=7.04 Hz, 3H), 1.48-1.63 (m, 4H),1.68-2.09 (m, 8H), 2.19 (br d, J=17.22 Hz, 1H), 2.49 (br s, 3H), 2.33(br s, 3H), 2.42 (br s, 1H), 2.55-2.70 (m, 2H), 2.77-3.04 (m, 6H), 3.08(s, 3H), 3.15 (br s, 1H), 3.54 (br s, 1H), 3.66 (br s, 1H), 3.74-3.96(m, 2H), 3.95-3.95 (m, 1H), 4.02 (d, J=12.32 Hz, 1H), 4.09-4.21 (m, 2H),5.51 (br d, J=17.02 Hz, 1H), 5.64 (br d, J=16.82 Hz, 1H), 7.11-7.17 (m,2H), 7.21 (dd, J=8.51, 2.25 Hz, 1H), 7.38 (d, J=7.82 Hz, 1H), 7.67 (d,J=8.61 Hz, 1H), 9.12 (br s, 1H).

Example 19(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (12 mg, 0.019 mmol) and 1-(oxetan-3-yl)piperazine (26.6mg, 0.187 mmol) in DCM (374 μL) at room temperature was added a few dropof titanium (IV) isopropoxide. The mixture was stirred at roomtemperature for 8 h and sodium triacetoxyborohydride (15.84 mg, 0.075mmol) was added slowly over 1 min. The reaction was stirred forovernight and quenched with 5 mL of 1 N HCl solution. The aqueous phasewas extracted with DCM (3×). The combined organic extracts wereconcentrated. The residue was purified by prep-HPLC to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 768.2 (M+H)⁺. ¹HNMR (400 MHz, MeOH-d₄) δ ppm 1.11 (d, J=6.65 Hz, 3H), 1.39 (d, J=7.24Hz, 3H), 1.44-1.58 (m, 1H) 1.64-2.01 (m, 6H), 2.03-2.27 (m, 2H),2.29-2.43 (m, 2H) 2.45-2.56 (m, 1H), 2.32-3.04 (m, 7H), 3.35-3.67 (m,6H), 3.35-3.65 (m, 6H), 3.72-3.93 (m, 4H), 4.03-4.10 (m, 1H), 4.12-4.28(m, 2H), 4.61 (t, J=6.16 Hz, 2H), 4.69-4.77 (m, 2H), 5.78-5.90 (m, 2H),7.12 (d, J=1.96 Hz, 1H), 7.15-7.20 (m, 1H), 7.21-7.26 (m, 2H), 7.70 (d,J=8.41 Hz, 1H).

Example 20(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide

To a solution of (3R,4S)-1-methoxy-4-methylhept-6-ene-3-sulfonamide(4.94 g, 22.34 mmol) in DCM (80 mL) was added(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylicacid (6.8 g, 11.5 mmol), 4-(dimethylamino) pyridine (4.20 g, 34.4 mmol),triethylamine (3.2 mL, 23.0 mmol), and1-β-dimethylaminopropyl)-3-ethylcarbodiimide HCl (6.6 g, 34.4 mmol). Theresulting mixture was stirred at room temperature under nitrogen for 20h. The reaction was quenched with 2 N HCl (5 mL) and diluted with water(30 mL). The aqueous layer was extracted with DCM (2×40 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. The crude product was purified by column chromatography(330 g of silica, 0% to 40% acetone in heptane) to obtain(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamideas light brown solid (6.1 g). ¹H NMR (DICHLOROMETHANE-d₂) δ 10.43 (br.S., 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.19 (d, J=7.8Hz, 2H), 7.10 (s, 1H), 5.67-5.87 (m, 2H), 5.19 (d, J=17.2 Hz, 1H),5.01-5.12 (m, 3H), 4.60 (d, J=13.7 Hz, 1H), 4.10-4.20 (m, 1H), 3.96-4.07(m, 3H), 3.89 (d, J=14.7 Hz, 1H), 3.53 (t, J=6.4 Hz, 1H), 3.43-3.50 (m,1H), 3.34-3.42 (m, 1H), 3.19-3.25 (m, 2H), 3.13 (s, 1H), 2.82-2.92 (m,1H), 2.73-2.82 (m, 2H), 2.55-2.69 (m, 1H), 2.37-2.48 (m, 1H), 2.33 (br.S., 1H), 2.04-2.22 (m, 3H), 1.91-2.01 (m, 4H), 1.76-1.91 (m, 2H),1.62-1.74 (m, 1H), 1.54-1.61 (m, 1H), 1.41 (t, J=12.8 Hz, 1H), 1.07 (dd,J=11.2, 7.0 Hz, 3H). MS (ESI, +ve ion) m/z 672.4 (M+H)⁺.

Step 2:(S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide

To a solution of(1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide(6.1 g, 9.07 mmol) in DCM (70 mL) at 0° C. was added Dess-Martinperiodinane (4.5 g, 10.61 mmol). After the addition, the ice bath wasremoved and the resulting mixture was warmed up to room temperature andstirred for 20 h. The reaction was quenched with 10% sodium thiosulfate(5 mL) and stirred for 30 min. The resulting mixture was washed withsaturated NaHCO₃(30 mL). The aqueous layer was extracted with DCM (2×50mL). The combined organic layers were dried over MgSO₄, filtered, andconcentrated. The crude product was purified by column chromatography(330 g of silica, 0% to 40% acetone in heptane) to obtain(S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamideas light brown foam. ¹H NMR (DICHLOROMETHANE-d₂) δ 9.25-9.54 (m, 1H),7.70-7.76 (m, 1H), 7.44-7.51 (m, 1H), 7.14-7.21 (m, 1H), 7.03-7.13 (m,2H), 5.85-6.03 (m, 2H), 4.13-4.22 (m, 1H), 4.01-4.12 (m, 2H), 3.85-3.99(m, 1H), 3.72-3.81 (m, 1H), 3.58-3.70 (m, 2H), 3.29-3.33 (m, 7H),3.17-3.27 (m, 6H), 2.94-3.04 (m, 3H), 2.83-2.93 (m, 4H), 2.73-2.80 (m,2H), 2.51-2.64 (m, 1H), 2.32-2.41 (m, 1H), 2.23-2.31 (m, 1H), 2.05-2.12(m, 2H), 1.97-2.05 (m, 1H), 1.87-1.96 (m, 2H), 1.76-1.87 (m, 2H),1.61-1.70 (m, 2H), 1.51-1.59 (m, 5H), 1.40-1.51 (m, 2H), 1.04-1.11 (m,5H), 0.96-1.02 (m, 3H). MS (ESI, +ve ion) m/z 670.2 (M+H)⁺.

Step 3:(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide

To a solution of(S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide(2.2 g, 3.28 mmol) in 1,2-dichloroethane (1200 mL) under nitrogen wasadded Hoveyda-Grubbs catalyst 2^(nd) generation (0.206 g, 0.328 mmol).The resulting mixture was heated at 55° C. for 20 h. The reaction wascooled to room temperature and concentrated. The crude product waspurified by column chromatography (220 g of silica, 0% to 30% acetone inheptane) to obtain(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide as pale yellow solid (1.5 g). ¹H NMR(DICHLOROMETHANE-d₂) δ 8.69 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.20 (d,J=8.4 Hz, 1H), 7.08-7.18 (m, 3H), 6.71-6.82 (m, 1H), 5.86-5.96 (m, 1H),4.44 (dd, J=14.1, 8.4 Hz, 1H), 4.14 (d, J=12.1 Hz, 1H), 3.99 (d, J=12.1Hz, 1H), 3.92 (d, J=15.3 Hz, 1H), 3.85-3.89 (m, 1H), 3.73-3.82 (m, 1H),3.70 (dd, J=8.0, 5.1 Hz, 1H), 3.59-3.66 (m, 1H), 3.42 (s, 3H), 3.39 (d,J=14.7 Hz, 1H), 2.94 (dd, J=14.0, 3.8 Hz, 1H), 2.82-2.90 (m, 1H),2.72-2.82 (m, 2H), 2.35-2.45 (m, 1H), 2.26-2.34 (m, 1H), 2.09-2.19 (m,3H), 1.97-2.06 (m, 2H), 1.75-1.94 (m, 5H), 1.37-1.48 (m, 1H), 1.18 (d,J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 642.2 (M+H)⁺.

Step 4:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

An oven dry 50 mL 3-neck flask, which was equipped with stir bar andtemperature probe, was added 1,3-dithiane (0.890 g, 7.40 mmol) and THF(15 mL). The resulting mixture was cooled between −20 to −30° C. andn-butyllithium solution (2.5 M in hexanes, 2.7 mL, 6.75 mmol) was addeddropwise via syringe. The resulting mixture was stirred at −20° C. for30 min, cooled below −70° C. and stirred for 20 min. To this reactionwas added lanthanum(III) chloride lithium chloride complex (0.6 M inTHF, 5.6 mL, 3.36 mmol, Strem Chemical, Newbury Port, Mass.) dropwisevia syringe (internal temperature was kept below −70° C.). After 10 min,(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (0.430 g, 0.670 mmol) in THF (5 mL) was added dropwisevia syringe (internal temperature was kept below −70° C.). The reactionwas stirred at −70° C. for 15 min after the addition. The reaction wasquenched with saturated NH₄Cl (3 mL), warmed to room temperature andpartitioned between EtOAc (60 mL) and water (30 mL). The organic layerwas dried over MgSO₄, filtered, and concentrated. Purification by columnchromatography (80 g of silica, 0% to 30% acetone in heptane) gave(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as white solid (0.350 g). ¹H NMR (DICHLOROMETHANE-d₂) δ9.24 (br. S., 1H), 7.65-7.73 (m, 1H), 7.35-7.41 (m, 1H), 7.19 (d, J=7.8Hz, 2H), 7.11 (s, 1H), 5.76-5.87 (m, 1H), 5.60-5.71 (m, 1H), 4.61 (dd,J=13.5, 4.9 Hz, 1H), 4.12-4.22 (m, 2H), 3.94-4.03 (m, 2H), 3.89 (d,J=14.5 Hz, 1H), 3.53-3.63 (m, 2H), 3.44 (d, J=14.5 Hz, 1H), 3.32 (s,3H), 2.94-3.04 (m, 2H), 2.85-2.93 (m, 4H), 2.73-2.84 (m, 3H), 2.54-2.70(m, 2H), 2.17-2.33 (m, 2H), 2.04-2.13 (m, 4H), 1.87-2.00 (m, 3H),1.71-1.83 (m, 3H), 1.64 (dt, J=18.6, 9.5 Hz, 1H), 1.47 (d, J=14.9 Hz,1H), 1.15 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 762.2 (M+H)⁺.

Step 5:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 15 mL flask was added(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.350 g, 0.459 mmol) and THF (15.0 mL). The mixture wascooled to 0° C. and sodium hydride (60 weight percent in oil, 0.165 g,4.13 mmol) was added. The ice bath was removed after the addition andthe mixture was stirred at room temperature for 20 min then iodomethane(0.520 mL, 8.37 mmol) was added. The mixture was stirred at roomtemperature for 2 h then quenched with water (5 mL). The resultingmixture was partitioned between EtOAc (50 mL) and water (20 ml). Theorganic layers was dried over MgSO₄, filtered, and concentrated.Purification by column chromatography (40 g of silica, 0% to 30% acetonein heptane) gave(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as white solid. ¹H NMR (DICHLOROMETHANE-d₂) δ 9.20 (br.S., 1H), 7.69 (d, J=8.4 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.16-7.22 (m,2H), 7.11 (s, 1H), 5.73-5.86 (m, 1H), 5.49-5.60 (m, 1H), 4.82 (dd,J=14.0, 5.0 Hz, 1H), 4.37 (s, 1H), 4.09-4.20 (m, 2H), 3.99 (d, J=12.3Hz, 1H), 3.91 (d, J=14.5 Hz, 1H), 3.56-3.71 (m, 2H), 3.40-3.50 (m, 1H),3.33 (s, 3H), 3.22 (s, 3H), 3.09 (br. S., 1H), 2.92-3.00 (m, 1H),2.83-2.91 (m, 4H), 2.75-2.83 (m, 2H), 2.66-2.74 (m, 1H), 2.63 (br. S.,1H), 2.17-2.33 (m, 2H), 2.04-2.14 (m, 3H), 1.91 (td, J=11.7, 3.6 Hz,4H), 1.71-1.80 (m, 1H), 1.62-1.70 (m, 2H), 1.54-1.62 (m, 1H), 1.39-1.49(m, 1H), 1.15 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 776.2 (M+H)⁺.

Step 6:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

To a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.250 g, 0.322 mmol) in acetonitrile (12.0 mL) wasadded calcium carbonate (0.161 g, 1.610 mmol), water (3.00 mL), andiodomethane (0.250 mL, 4.02 mmol). The resulting mixture was heated at40° C. for 20 h. The reaction was partitioned between water (20 mL) andDCM (50 mL). The aqueous layer was extracted with DCM (30 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. The purification by column chromatography (24 g of silica,0% to 30% acetone in heptane) gave(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24-]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide as white solid (0.130 g). ¹H NMR (DICHLOROMETHANE-d₂) δ9.74 (s, 1H), 9.50 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.47 (d, J=7.8 Hz,1H), 7.21 (d, J=8.0 Hz, 2H), 7.12 (d, J=2.2 Hz, 1H), 5.69 (d, J=16.2 Hz,1H), 5.38-5.47 (m, 1H), 4.42 (dd, J=14.0, 8.5 Hz, 1H), 4.19 (d, J=12.3Hz, 1H), 4.04 (d, J=12.1 Hz, 1H), 3.87 (d, J=14.7 Hz, 1H), 3.60 (td,J=8.7, 4.9 Hz, 1H), 3.46-3.54 (m, 2H), 3.38-3.45 (m, 1H), 3.31 (s, 3H),3.06 (s, 3H), 2.96 (dd, J=14.1, 5.9 Hz, 1H), 2.74-2.90 (m, 4H), 2.46(ddd, J=11.2, 7.1, 3.7 Hz, 1H), 2.21-2.28 (m, 1H), 2.11-2.20 (m, 1H),1.97-2.08 (m, 2H), 1.81-1.96 (m, 5H), 1.67-1.79 (m, 1H), 1.55-1.66 (m,1H), 1.40-1.50 (m, 1H), 1.14 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z686.2 (M+H)⁺.

Step 7:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.080 g, 0.117 mmol) inDCM (4.0 mL) was added (S)-octahydropyrazino[2,1-c][1,4]oxazine (0.093g, 0.653 mmol) in DCM (4.0 mL) and acetic acid (1 drop). The mixture wasstirred at room temperature under nitrogen for 1 h. Sodiumtriacetoxyborohydride (0.100 g, 0.472 mmol) was added and the mixturewas stirred at room temperature for 1 h. The reaction was partitionedbetween water (10 mL) and DCM (20 mL). The aqueous layer was extractedwith DCM (20 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated. Purification by column chromatography (24 gof silica, 0% to 10% MeOH in DCM) gave(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as white solid (0.066 g). ¹H NMR (DICHLOROMETHANE-d₂) δ7.70 (d, J=8.4 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H),7.08-7.16 (m, 2H), 5.53-5.66 (m, 2H), 4.13-4.19 (m, 1H), 4.02-4.12 (m,2H), 3.74-3.83 (m, 2H), 3.65-3.73 (m, 1H), 3.53-3.63 (m, 3H), 3.46 (d,J=14.7 Hz, 1H), 3.32 (s, 4H), 2.98-3.10 (m, 7H), 2.74-2.85 (m, 2H), 2.72(d, J=6.1 Hz, 1H), 2.52-2.64 (m, 3H), 2.46 (d, J=16.8 Hz, 3H), 2.23-2.37(m, 2H), 2.06-2.15 (m, 1H), 1.96-2.03 (m, 2H), 1.85-1.94 (m, 4H),1.72-1.81 (m, 2H), 1.45-1.63 (m, 6H), 1.08 (d, J=6.8 Hz, 3H). Oneexchangeable proton was not observed. MS (ESI, +ve ion) m/z 812.4(M+H)⁺.

Example 21(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24-]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.140 g, 0.204 mmol) in DCM (5.0 mL) was added(R)-octahydro-1H-pyrido[1,2-a]pyrazine (0.160 g, 1.141 mmol) in DCM (1mL) and AcOH (2 drops). The mixture was stirred at room temperatureunder nitrogen for 1 h then treated with sodium triacetoxyborohydride(0.173 g, 0.816 mmol). The resulting mixture was stirred for 1 h thenpartitioned between water (10 mL) and DCM (20 mL). The aqueous layer wasextracted with DCM (20 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated. Purification by column chromatography(24 g of silica, 0% to 10% MeOH in DCM) gave(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as white solid (0.120 g). ¹H NMR (DICHLOROMETHANE-d₂) δ7.69-7.76 (m, 1H), 7.42-7.50 (m, 1H), 7.18 (dd, J=8.5, 2.1 Hz, 1H),7.04-7.14 (m, 2H), 5.77 (br. S., 2H), 4.17 (d, J=12.9 Hz, 1H), 4.00-4.13(m, 2H), 3.77 (d, J=14.5 Hz, 1H), 3.64-3.73 (m, 1H), 3.57 (d, J=9.2 Hz,2H), 3.35-3.47 (m, 1H), 3.21-3.34 (m, 5H), 3.09 (br. S., 3H), 2.99 (br.S., 1H), 2.83-2.95 (m, 2H), 2.65-2.82 (m, 5H), 2.55 (br. S., 2H),2.25-2.44 (m, 3H), 2.09-2.21 (m, 1H), 1.97-2.08 (m, 3H), 1.89 (d, J=19.2Hz, 4H), 1.61-1.73 (m, 4H), 1.38-1.51 (m, 4H), 1.29-1.35 (m, 1H), 1.17(br. S., 2H), 1.02 (d, J=6.8 Hz, 4H). One exchangeable proton was notobserved. MS (ESI, +ve ion) m/z 810.4 (M+H)⁺.

Example 33(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

A 2-dram vial was charged with(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-12′-ethyl-7′-methoxy-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (27 mg, 0.037 mmol; Accessed via General Methods 1(R¹=H, using(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid and (R)-hept-6-ene-3-sulfonamide) and General Methods 5 (usingMeI)), a magnetic stir bar, acetonitrile (820 μL) and water (205 μL). Tothe resulting suspension was added calcium carbonate (18.5 mg, 0.185mmol) and iodomethane (23 μL, 0.37 mmol). The vial was sealed and themixture stirred at 45° C. Additional iodomethane (10 equiv) was addedafter 2.5 h, 19 h, 23 h, and 27 h. After a 51 h reaction time, thereaction was quenched by adding saturated aqueous ammonium chloride (1mL) and water (1 mL). The mixture was extracted with EtOAc (3×2 mL) andthe combined organic extracts were washed with brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure toafford a mixture of(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide in a 3:1 ratio that was carried forward in the next stepwithout purification.

Step 2:(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A 1 mL vial was charged with a 3:1 mixture of(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.022 g, 0.034 mmol),(R)-octahydro-1H-pyrido[1,2-a]pyrazine (26.5 mg, 0.189 mmol; AurumPharmatech, Franklin Park, N.J.), a magnetic stir bar, and1,2-dichloroethane (343 μL). The resulting mixture was stirred for 1 hbefore the addition of sodium triacetoxyborohydride (3.6 mg, 0.017mmol). After 45 min, a second portion of sodium triacetoxyborohydride(3.6 mg, 0.017 mmol) was added and the reaction was continued for anadditional 2 h before a third portion of sodium triacetoxyborohydride(3.6 mg, 0.017 mmol) was added. After an additional 3 h, the reactionwas quenched by adding methanol.(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide was isolated as the corresponding TFA salt afterpurification via RP-HPLC (Column: Phenomenex Luna, C18, 150×21 mm;Solvent: A=water (0.1% TFA), B=(R) (0.1% TFA), 30 mL/min, 30% B to 100%B over 18 min then 2 min at 100% B): 5.2 mg (0.006 mmol, 17% yield); MS(ESI, +ve ion) m/z 779.3 (M+H)⁺.

Example 34(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((2-(4-morpholinyl)ethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-15′-oxo-7′-methoxy-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (52 mg, 0.081 mmol) and 2-morpholinoethanamine (106 μL,0.811 mmol) in THF (810 μL) was stirred at ambient temperature for 90min. Sodium cyanotrihydroborate (25.5 mg, 0.405 mmol) and acetic acid(93 μL, 1.6 mmol) were added and the reaction mixture was stirred atambient temperature for 1 h. The reaction mixture was diluted with EtOAc(2 mL) and washed with saturated aqueous sodium bicarbonate (5 mL); thelayers were partitioned and the aqueous layer was washed with EtOAc (2×5mL). The organic extracts were combined, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to afford an off-white solid.(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((2-(4-morpholinyl)ethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide was isolated as the corresponding TFA salt afterpurification via RP-HPLC (Column: Phenomenex Luna, C18, 150×21 mm;Solvent: A=water (0.1% TFA), B=(R) (0.1% TFA), 30 mL/min, 30% B to 100%B over 18 min then 2 min at 100% B): 41.8 mg (0.048 mmol, 59% yield); MS(ESI, +ve ion) m/z 755.2 (M+H)⁺.

Example 99(1S,3′R,6′R,7′S,8′E,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a room temperature mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.050 g, 0.080 mmol) and (R)-morpholin-3-ylmethanolhydrochloride (0.124 g, 0.807 mmol; J&W Pharmlab, Levittown, Pa.) wasadded N,N-diisopropylethylamine (0.230 mL, 1.32 mmol) via syringe. After30 min, 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.400 mL,0.400 mmol) and acetic acid (0.100 mL, 1.73 mmol) were added and thereaction was allowed to stir at room temperature overnight. The reactionmixture was quenched with satd NH₄Cl and the aqueous layer was extractedwith DCM (3×). The combined organic layers were evaporated onto silicagel and purified by flash chromatography (Isco, (4 gram HP)) elutingwith 0% to 100% 2 M NH₃ in MeOH in DCM to give 70 mg of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a white crystalline solid. (ESI, +ve ion) m/z 728.3(M+1)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide

To a room temperature solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide in tetrahydrofuran (0.3 mL) was added 60% sodium hydridein mineral oil (0.011 g, 0.275 mmol) as a solid. After 30 min themixture was cooled (0° C.) and treated with1-(p-toluenesulfonyl)imidazole (0.064 g, 0.288 mmol) and the reactionwas allowed to warm to room temperature overnight. The reaction mixturewas quenched with saturated NH₄Cl and the aqueous layer was extractedwith EtOAc (3×). The combined organic layers were evaporated onto silicagel and purified by flash chromatography (Isco, (4 gram HP)) elutingwith 2 M NH₃ in MeOH:CH₂Cl₂ (0:1→1:9) to afford(1S,3′R,6′R,7′S,8′E,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide (2.1 mg, 9%) as a tan crystalline solid. MS (ESI, +veion) m/z 710.3 (M+1)⁺.

Example 100(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(1H-imidazol-1-ylmethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a room temperature mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.052 g, 0.083 mmol) and 3(S)-hydroxymethylmorpholine(0.099 g, 0.845 mmol; J&W Pharmlab, Levittown, Pa.) in tetrahydrofuran(2 mL) was added N,N-diisopropylethylamine (0.250 mL, 1.437 mmol). After1 h, 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.450 mL, 0.450mmol) and acetic acid (0.100 mL, 1.73 mmol) were added and the reactionwas stirred overnight. The reaction mixture was quenched with pH 7buffer and the aqueous layer was extracted with DCM (3×). The combinedorganic layers were evaporated onto silica gel and purified by flashchromatography (Isco (4 g)) eluting with 25% EtOH/EtOAc:heptane(0:1→1:1) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (46 mg, 76%) as a white crystalline solid. (ESI, +veion) m/z 728.2 (M+1)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(1H-imidazol-1-ylmethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a room temperature solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide in tetrahydrofuran (1 mL) was added sodium hydride(0.020 g, 0.51 mmol) as a solid. After 30 min the reaction was cooled(0° C.) and treated with 1-(p-toluenesulfonyl)imidazole (0.112 g, 0.505mmol). After stirring overnight the reaction mixture was quenched withpH 7 buffer and the aqueous layer was extracted with DCM (3×). Thecombined organic layers were evaporated onto silica gel and purified byflash chromatography (Isco (4 g)) eluting with 25% EtOH/EtOAc:heptane(0:1→1:0) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(1H-imidazol-1-ylmethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (27 mg, 55%) as a white crystalline solid. (ESI, +veion) m/z 778.3 (M+1)⁺.

Example 105(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.010 g, 0.013 mmol) and palladium, 10 wt. % (drybasis) on activated carbon, wet, degussa type (0.005 g, 2.3 μmol) inEtOAc (1 mL) was stirred at room temperature under hydrogen (18 psig)overnight. The reaction was filtered through a pad of Celite and the padwas washed with EtOAc. The filtrate was concentrated under reducedpressure, diluted with MeOH and purified by reverse-phase HPLC (Gilson;Gemini-NX C18 AXIA, 100×50 mm column) eluting with 0.1% TFA-H₂O:0.1% TFACH₃CN (9:1→1:9). The fractions containing the desired product werecombined and partitioned between pH 7 buffer (1 M K₂HPO₄/KH₂PO₄)/EtOAc.The aqueous layer was extracted with EtOAc (3×) and the combined organiclayers were washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (6.5 mg, 68%) as a white crystalline solid. (ESI, +veion) m/z: 747.3 (M+1)⁺.

Example 124(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-4″,11′,12′-trimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

Calcium carbonate (2.60 g, 18.5 mmol) and iodomethane (1 M in TBME; 18.5mL, 37.1 mmol) were sequentially added to a solution of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (2.66 g, 3.71 mmol) in acetonitrile (44 mL)/water (6.5mL) at 50° C.; the reaction mixture was stirred at 50° C. for 16 h. Theslurry was filtered to remove any excess calcium carbonate, and thefiltrate was concentrated. The solid was diluted with EtOAc (150 mL);the milky mixture was poured off; the remaining solid was diluted withDCM/IPA (3:2, 200 mL), and the combined organics were partitioned withsat. aq. NH₄Cl (100 mL). The organic layer was separated, solublizedwith MeOH, dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was adsorbed onto silica gel and was purified viaautomated flash chromatography (silica gel, 0% to 50% EtOAc/heptanew/0.3% AcOH) to give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (396 mg, 0.631 mmol, 17% yield) and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (0.810, 1.29 mmol, 35% yield), both as white solids. MS(ESI, +ve) m/z 627.2 (M+1)⁺ for both.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((methylamino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (48 mg, 0.077 mmol), methanamine hydrochloride (91 mg,1.3 mmol), and DIPEA (227 μL, 1.30 mmol) in DCM (383 μL)/MeOH (580 μL)was stirred at room temperature for 15 min; sodium cyanotrihydroborate(14 mg, 0.23 mmol) was then added. The slurry was stirred at roomtemperature for 30 min. The reaction mixture was diluted with DCM (50mL), added to a separatory funnel, and washed with water (50 mL); theorganic layer was separated, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The crude product was adsorbed onto silica geland was purified via automated flash chromatography (silica gel, 0% to20% MeOH/DCM) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((methylamino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (14 mg, 0.022 mmol, 29% yield) as a white film. MS (ESI,+ve) m/z 642.2 (M+1)⁺.

Step 3:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-4″,11′,12′-trimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide

Cesium carbonate (85 mg, 0.26 mmol) was added to a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((methylamino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (14 mg, 0.022 mmol) and 1,2-dibromoethane (8 μL, 0.09mmol) in DMF (0.22 mL) at ambient temperature. The reaction mixture wasstirred at 70° C. for 16 h. 1-Tosyl-1H-imidazole (4.8 mg, 0.022 mmol)and sodium hydride (60% in mineral oil; 0.5 mg, 0.02 mmol) were added tothe reaction mixture which was then stirred at ambient temperature for20 min. The reaction mixture was diluted with EtOAc (50 mL), added to aseparatory funnel, and washed with saturated, aqueous sodium bicarbonate(2×50 mL); the organic layer was separated, dried over anhydrous Na₂SO₄,and concentrated in vacuo. The crude product was adsorbed onto silicagel and was purified via automated flash chromatography (silica gel, 0%to 10% MeOH/DCM) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-4″,11′,12′-trimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide (2 mg, 3 μmol, 14% yield) as a light yellow oil. MS(ESI, +ve) m/z 668.3 (M+1)⁺.

Example 125(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-((tert-butylamino)methyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (99 mg, 0.16 mmol) and 2-methylpropan-2-amine (115 mg,1.58 mmol) in THF (1.6 mL) was stirred at ambient temperature for 1.5 h;sodium cyanotrihydroborate (50 mg, 0.79 mmol) and acetic acid (181 μL,3.16 mmol) were added, and the reaction mixture was stirred at ambienttemperature for 1 h. The reaction mixture was diluted with EtOAc (75mL), added to a separatory funnel, and washed with saturated, aqueoussodium bicarbonate (100 mL); the organic layer was separated, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The crude product wasadsorbed onto silica gel and was purified via automated flashchromatography (silica gel, 0% to 10% MeOH/DCM) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-((tert-butylamino)methyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (53 mg, 0.077 mmol, 49% yield) as a white solid. MS(ESI, +ve) m/z 684.3 (M+1)⁺.

Example 126(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)(1-methylethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (68 mg, 0.11 mmol) and 2-(isopropylamino)ethanol(Enamine, Monmouth Jct, N.J.; 112 mg, 1.08 mmol) in THF (1.1 mL) wasstirred at ambient temperature for 2.5 h; sodium cyanotrihydroborate (34mg, 0.54 mmol) and acetic acid (0.1 mL, 2.2 mmol) were added, and thereaction mixture was stirred at ambient temperature for 1 h. Thereaction mixture was diluted with EtOAc (75 mL), added to a separatoryfunnel, and washed with saturated, aqueous sodium bicarbonate (100 mL);the organic layer was separated, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The crude product was adsorbed onto silica geland was purified via automated flash chromatography (silica gel, 0% to8% MeOH/DCM) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)(1-methylethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (20 mg, 0.028 mmol, 26% yield) as awhite solid. MS (ESI, +ve) m/z 714.2 (M+1)⁺.

Example 127(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-4″-(1-methylethyl)-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide

Sodium hydride (60% in mineral oil; 3 mg, 0.07 mmol) was added to asolution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)(1-methylethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (17 mg, 0.024 mmol) and 1-tosyl-1H-imidazole (6.9 mg,0.031 mmol) in THF (0.24 mL) at 0° C.; the reaction mixture was stirredat 0° C. for 15 min. The reaction mixture was diluted with EtOAc (75mL), added to a separatory funnel, and washed with saturated, aqueousammonium chloride (100 mL); the organic layer was separated, dried overanhydrous Na₂SO₄, and concentrated in vacuo. A solution of the crudeproduct in DCM was loaded onto the column and was purified via automatedflash chromatography (silica gel, 0% to 6% MeOH/DCM) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-4″-(1-methylethyl)-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide (6 mg, 9 μmol,36% yield) as a white solid. MS (ESI, +ve) m/z: 696.3 (M+1)⁺.

Example 128(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione13′,13′-dioxide or(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione13′,13′-dioxide

Step 1: methyl((1S,3′R,6′R,7′R,8′E,1l'S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0-119,24]pentacosa[8,16,18,24]tetraen]-7′-yl)acetateand methyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate

A solution of methyl acetate (0.172 mL, 2.17 mmol) in THF (1 mL) wasadded dropwise to a stirred solution of lithium diisopropylamide (1.0 Msolution in hexanes/tetrahydrofuran, 2.17 mL, 2.17 mmol) in THF (1 mL)at −78° C. The mixture was stirred at −78° C. for 0.5 h before asolution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (216 mg, 0.362 mmol) in THF (2 mL) was added slowly viasyringe. The reaction mixture was stirred at −78° C. for 1.5 h beforebeing allowed to warm to room temperature and quenched with water (15mL). The mixture was extracted with EtOAc (25 mL). The organic layer wasseparated, washed with 1 M aqueous HCl (15 mL), washed with brine (15mL), dried over MgSO₄, filtered, and concentrated in vacuo to give acrude mixture of methyl((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetateand methyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate(246 mg, 0.366 mmol, 101% yield) as a yellow solid that was useddirectly in the next step. MS (ESI, +ve ion) m/z 671.3 (M+H)⁺.

Step 2:((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid and((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid

Lithium hydroxide (2.0 M aqueous, 0.453 mL, 0.905 mmol) was added to astirred solution of methyl((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetateand methyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate(243 mg, 0.362 mmol) in tetrahydrofuran (7 mL). The reaction mixture wasstirred at room temperature for 16 h. The reaction mixture was quenchedwith saturated aqueous NH₄Cl (30 mL) and extracted three times withEtOAc (50 mL). The combined organic layers were washed with brine (50mL), dried over MgSO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0% to 100%EtOAc with 0.3% AcOH as a modifier in heptane) gave the desired productcontaminated with AcOH. The isolated product was azeotroped with tolueneto give a mixture of((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid and((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid (66 mg, 0.100 mmol, 27.7% yield) as a white solid. MS (ESI, +veion) m/z 657.2 (M+H)⁺.

Step 3:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2‘’H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione13′,13′-dioxide or(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione13′,13′-dioxide

A mixture of((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid and((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid (66 mg, 0.100 mmol), triethylamine (0.031 mL, 0.221 mmol), anddiphenylphosphoryl azide (0.024 mL, 0.110 mmol) in tert-butanol (2 mL)was refluxed for 2.5 h. The reaction mixture was concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0% to 100%EtOAc with 0.3% AcOH as a modifier in heptane) provided(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2‘’H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione13′,13′-dioxide or(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione13′,13′-dioxide (30 mg, 0.046 mmol, 45.7% yield) as a white solid. MS(ESI, +ve ion) m/z 654.2 (M+H)⁺.

Example 138(1S,3′R,6′R,7′R,8′E,11′S,12′R)-4″-benzyl-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A mixture of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (199 mg, 0.317 mmol) and 2-aminoethanol (322 mg, 5.27mmol) was stirred in dichloromethane (6 mL) for 20 min before aceticacid (0.366 mL, 6.35 mmol) and sodium cyanoborohydride (59.8 mg, 0.952mmol) were added. The reaction mixture was stirred at room temperaturefor 17 h. The reaction mixture was quenched with saturated aqueous NH₄Cl(40 mL) and extracted with EtOAc (50 mL). The organic layer wasseparated, washed with brine (30 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. Chromatographic purification of the residue(silica gel, 0% to 10% 2 M ammonia in MeOH in DCM) provided(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (115 mg, 0.171 mmol, 53.9% yield) as a white solid. MS(ESI, +ve ion) m/z 672.2 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide

Sodium hydride (60% dispersion in mineral oil, 20.5 mg, 0.513 mmol) wasadded to a stirred suspension of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (115 mg, 0.171 mmol) in tetrahydrofuran (5 mL) at roomtemperature. The mixture was stirred for 20 min before being cooled to0° C., followed by addition of 1-(p-toluenesulfonyl)imidazole (38.0 mg,0.171 mmol). The reaction mixture was stirred at 0° C. for 5 h. Thereaction mixture was quenched with saturated aqueous NH₄Cl (20 mL) andextracted with EtOAc (30 mL). The organic layer was separated, washedwith brine (20 mL), dried over MgSO₄, filtered, and concentrated invacuo. Chromatographic purification of the residue (silica gel, 0% to10% 2 M ammonia in MeOH in DCM) provided(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2‘’-[1,4]oxazinan]-15′-one 13′,13′-dioxide (67 mg, 0.102 mmol, 60% yield)as a white solid. MS (ESI, +ve ion) m/z 654.2 (M+H)⁺.

Step 3:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-4″-benzyl-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide (17 mg, 0.026 mmol), (bromomethyl)benzene (3.40 μl,0.029 mmol), and triethylamine (7.95 μl, 0.057 mmol) were mixed inacetonitrile (0.25 mL). The reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was quenched with saturatedaqueous NH₄Cl (10 mL) and extracted with EtOAc (15 mL). The organiclayer was separated, washed with brine (10 mL), dried over MgSO₄,filtered, and concentrated in vacuo. Chromatographic purification of theresidue (silica gel, 0 to 10% 2 M ammonia in MeOH in DCM) provided(1S,3′R,6′R,7′R,8′E,11′S,12′R)-4″-benzyl-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide (9 mg, 0.012 mmol, 47% yield) as a white solid. MS (ESI,+ve ion) m/z 744.3 (M+H)⁺.

Example 151(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-diathian-2-yl)-7′-(2-methoxyethoxy)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[napthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-2-methyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (460 mg, 0.641 mmol) in tetrahydrofuran (8 mL) was addedsodium hydride, 60% dispersion in mineral oil (679 mg, 19.24 mmol) inportions. After addition, the mixture was then stirred at roomtemperature under nitrogen for 10 min, then 2-bromoethyl methyl ether(1.809 mL, 19.24 mmol) was added. The resulting mixture was stirred atroom temperature for 14 h. The mixture was quenched with saturated NH₄Cl(150 mL) and was extracted with EtOAc (2×200 mL). The combined organicextracts were dried over MgSO₄ and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0% to 100%EtOAc/heptane) provided(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-(2-methoxyethoxy)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (391 mg, 0.504 mmol, 79% yield) as a light yellow solid.MS (ESI, +ve ion) m/z 699.2, 755.3 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

A solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-(2-methoxyethoxy)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (391 mg, 0.504 mmol) in acetonitrile (10 mL) and water(2.500 mL) was added methyl iodide (0.313 mL, 5.04 mmol) and calciumcarbonate (252 mg, 2.52 mmol). The resulting mixture was then stirred at50° C. for 14 h. The mixture was quenched with saturated NH₄Cl and wasextracted with EtOAc (2×100 mL). The combined organic extracts were thendried over MgSO₄ and concentrated in vacuo. Chromatographic purificationof the residue (silica gel, 0% to 100% EtOAc/heptane) provided(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (233 mg, 0.340 mmol, 67.4% yield) as a light yellowsolid. MS (ESI, +ve ion) m/z 685.3 (M+H)⁺.

Step 3: 2-methyl-2-propanyl(2R)-2-(((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate

A solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (55 mg, 0.080 mmol) and (R)-tert-butyl2-(aminomethyl)piperidine-1-carboxylate (172 mg, 0.803 mmol) in1,2-dichloroethane (0.8 mL) was stirred at room temperature for 14 h.Sodium triacetoxyborohydride (0.059 mL, 0.401 mmol) was added to themixture and the mixture was then stirred at room temperature for 1 h.The mixture was diluted with MeOH (5 mL) and silica gel was added. Themixture was concentrated and dried in vacuo. The solid mixture was thenpurified by silica gel column chromatography (solid loading, 0% to 100%EtOAc/heptane) provided 2-methyl-2-propanyl(2R)-2-(((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate(64 mg, 0.072 mmol, 90% yield) as a light yellow solid. MS (ESI, +veion) m/z 883.5 (M+H)⁺.

Step 4:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((((2R)-2-piperidinylmethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of 2-methyl-2-propanyl(2R)-2-(((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate(58 mg, 0.066 mmol) in dichloromethane (0.5 mL) was addedtrifluoroacetic acid (0.098 mL, 1.3 mmol). The resulting mixture wasthen stirred at room temperature for 2 h. The mixture was cooled to 0°C. and iPr₂Net (0.457 mL, 2.63 mmol) was added followed by1,2-dibromoethane (0.023 mL, 0.263 mmol) and DMA (0.1 mL). The resultingmixture was then stirred at room temperature for 72 h and at 50° C. for1 h. The mixture was concentrated in vacuo and chromatographicpurification of the residue (silica gel, 0% to 100% EtOAc/heptane)provided(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((((2R)-2-piperidinylmethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a colorless oil, which was used in the next step. MS(ESI, +ve ion) m/z 783.3 (M+H)⁺.

Step 5:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((((2R)-2-piperidinylmethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (51.4 mg, 0.066 mmol) in N, N-dimethylacetamide (0.4 mL)was added iPr₂Net (0.057 mL, 0.328 mmol) and 1,2-dibromoethane (0.028mL, 0.328 mmol). The resulting mixture was then stirred at roomtemperature for 14 h. Then, 1,2-dibromoethane (0.2 mL) was added and themixture was stirred at room temperature for 14 h then at 55° C. for 72h. The mixture was purified by silica gel column chromatography (0% to10% MeOH/DCM) provided(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (17 mg, 0.021 mmol, 32.0% yield) as a light yellowsolid. MS (ESI, +ve ion) m/z 809.2 (M+H)⁺.

Example 154(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-3-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1: 2-methyl-2-propanyl(2R)-2-(((((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-N,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate

To a solution of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (44 mg, 0.069 mmol) in 1,2-dichloroethane (1 mL) wasadded (R)-tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (147 mg,0.686 mmol). The resulting mixture was then stirred at room temperaturefor 1 h. Then, sodium triacetoxyborohydride (73 mg, 0.343 mmol) wasadded in portions. After addition, the mixture was then stirred at roomtemperature for 3 d. The mixture was purified by silica gel columnchromatography (0% to 20% MeOH/DCM) to provide 2-methyl-2-propanyl(2R)-2-(((((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate(57.6 mg, 0.069 mmol, 100% yield) as a light yellow solid, which wasused in the next step. MS (ESI, +ve ion) m/z 839.4 (M+H)⁺.

Step 2: 2-methyl-2-propanyl(2R)-2-(((chloroacetyl)(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate

To a solution of 2-methyl-2-propanyl(2R)-2-(((((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate(57.6 mg, 0.069 mmol) in dichloromethane (1.5 mL) at −78° C. undernitrogen was added chloroacetyl chloride (10.92 μL, 0.137 mmol) followedby iPr₂Net (0.036 mL, 0.206 mmol). After addition, the mixture was thenstirred at −78° C. for 1.5 h. Chloroacetyl chloride (0.022 mL) was addedand the mixture was stirred at −25° C. for 1 h and placed in a −20° C.freezer for 16 h. The mixture was quenched with MeOH (2 mL) andconcentrated in vacuo. Chromatographic purification (silica gel, 0% to100% EtOAc/heptane) provided 2-methyl-2-propanyl(2R)-2-(((chloroacetyl)(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate(62.8 mg, 0.069 mmol, 100% yield) as a light yellow solid. MS (ESI, +veion) m/z 937.3, 939.2 (M+Na)⁺.

Step 3:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-3-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of 2-methyl-2-propanyl(2R)-2-(((chloroacetyl)(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate(61.8 mg, 0.067 mmol) in dichloromethane (1 mL) was addedtrifluoroacetic acid (0.251 mL, 3.37 mmol). After addition, the mixturewas then stirred at room temperature for 17 min. The mixture was cooledto −78° C. and iPrNEt (0.704 mL, 4.05 mmol) was added dropwise. Afteraddition, the mixture was stirred at room temperature for 14 h. Themixture was purified by silica gel column chromatography (0% to 20%MeOH/DCM) followed by preparative HPLC (Phenomenex Gemini C18 column,150×30 mm, 10% to 100% 0.1% TFA in MeCN/H₂O) provided a desired productin a solution of MeCN/H₂O 0.1% TFA. The pH was adjusted to 7 with buffer(KH₂PO₄/K₂HPO₄) and extracted with EtOAc (2×10 mL). The combinedextracts were washed with brine, dried (Na₂SO₄), concentrated, and driedin vacuo to provide(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-3-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (33 mg, 0.042 mmol, 62.8% yield) as an off white solid.MS (ESI, +ve ion) m/z 779.3 (M+H)⁺.

Examples 176 and 177(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-N,N,11′,12′-tetramethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxamide13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-N,N,11′,12′-tetramethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxamide13′,13′-dioxide

Step 1:(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-15′-oxo-7′-methyoxy-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxylicacid 13′,13′-dioxide

To a 15-mL round-bottomed flask was added(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-15′-oxo-7′-methoxy-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (18 mg, 0.028 mmol, a mixture of two epimers) and2-methyl-2-butene (149 μL, 1.404 mmol) in tert-butanol (281 L) and water(281 μL). Potassium phosphate monobasic (38.2 mg, 0.281 mmol) and sodiumchlorite (25.4 mg, 0.281 mmol) was added to the solution. The solutionwas stirred at room temperature for 1 h. The reaction mixture wasdiluted with saturated Na₂SO₃ (5 mL) and extracted with DCM (3×10 mL).The organic extract was washed with saturated NaCl (10 mL) and driedover MgSO₄. The solution was filtered and concentrated in vacuo to givean off-white solid. The material was used in the next step withoutfurther purification. MS (ESI, +ve ion) m/z 657.2 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-N,N,11′,12′-tetramethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxamide13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-N,N,11′,12′-tetramethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxamide13′,13′-dioxide

To a 5-mL round-bottomed flask was added(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-15′-oxo-7′-methyoxy-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxylicacid 13′,13′-dioxide (13 mg, 0.020 mmol, a mixture of two epimers) anddiethylamine (2 M in THF, 39.6 μL, 0.079 mmol) in DCM (396 μL).1-Propanephosphonic acid cyclic anhydride (50 wt. % solution in ethylacetate, 62.9 μL, 0.099 mmol) was added at room temperature. Thesolution was stirred at room temperature for 2 h. The reaction mixturewas diluted with saturated NaHCO₃(5 mL) and extracted with EtOAc (2×10mL). The organic layer was concentrated. The crude material was furtherpurified by prep-HPLC to give two products. The first peak collected wasassigned to be Example 176 and the second peak was assigned to beExample 177. MS (ESI, +ve ion) m/z 684.2 (M+H)⁺ for both isomers.

Examples 193 and 213(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′-(HYDROXYMETHYL)-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′-(HYDROXYMETHYL)-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To a stirred ice-cooled solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (1.015 g, 1.700 mmol) and trimethylsulfonium iodide(0.364 g, 1.785 mmol) in dimethyl sulfoxide (4.0 mL) was dropwise addedpotassium tert-butoxide, 1.0 M solution in tetrahydrofuran (4.25 mL,4.25 mmol) under argon. The resulting mixture was stirred in the icebath for 5 min and at ambient temperature for 30 min. The crude reactionmixture was directly loaded onto a silica gel precolumn (25 g)previously covered with a layer of ammonium chloride and subjected tocombi-flash column chromatography on a 24 g ISCO gold column elutingwith 0% to 100% EtOAc/Hexanes followed by 5% to 20% MeOH/DCM to give anapproximately 3:1 mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.82 g, 1.3 mmol, 79% yield) as a white solid. MS (ESI,+ve ion) m/z 629.2 (M+1)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAENE]-7′-CARBALDEHYDE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAENE]-7′-CARBALDEHYDE13′,13′-DIOXIDE

To a stirred ice-cooled solution of a mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (180 mg, 0.286 mmol) in DCM (5.0 mL) was added underargon Dess-Martin periodinane (121 mg, 0.286 mmol) in one portion as asolid. The resulting mixture was stirred under argon at 0° C. for 10 minand at ambient temperature for a period of 3 h. The crude mixture wasdirectly loaded onto a silica gel precolumn (25 g) and subjected tocombi-flash column chromatography on a 12 g ISCO gold column elutingwith 0% to 20% MeOH/DCM to give 180 mg of an impure mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide as an off-white solid. It was taken onto the next stepwithout further purification. MS (ESI, +ve ion) m/z 627.2 (M+1)⁺.

Step 3:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-((9AS)-HEXAHYDROPYRAZINO[2,1-C][1,4]OXAZIN-8(1H)-YLMETHYL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-((9AS)-HEXAHYDROPYRAZINO[2,1-C][1,4]OXAZIN-8(1H)-YLMETHYL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

The title compounds were prepared from a mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide according to General Method 10.(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 193) was the second eluting epimer off thesilica gel column. MS (ESI, +ve ion) m/z 753.3 (M+1)⁺.

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 213) was the first eluting epimer off thesilica gel column. MS (ESI, +ve ion) m/z 753.3 (M+1)⁺.

Example 194(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-7′-(4-MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′-(HYDROXYMETHYL)-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

The title compound was obtained as a single stereoisomer from a silicagel column chromatography separation of an epimeric mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide eluting with 1% to 20% MeOH/DCM. The title compound wasthe second eluting epimer off the silica gel column. MS (ESI, +ve ion)m/z 629.3 (M+1)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAENE]-7′-CARBALDEHYDE13′,13′-DIOXIDE

The title compound was synthesized from(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide according to the protocol in Example 193 (Step 2). MS(ESI, +ve ion) m/z 627.4 (M+1)⁺.

Step 3:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-7′-(4-MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

The title compound was synthesized from(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide according to General Method 10. MS (ESI, +ve ion) m/z698.5 (M+1)⁺.

Example 270(4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-7′-YL)METHYL)-1-PIPERAZINYL)ACETICACID

To a stirred solution of methyl(4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)-1-piperazinyl)acetate(Example 269) (15 mg, 0.019 mmol) in MeOH (1.5 mL) and water (0.5 mL)was added lithium hydroxide hydrate (8.0 mg, 0.19 mmol). The resultingmixture was stirred at room temperature for 3 h. The residue was takenup in MeOH and subjected to preparative reverse-phase HPLC (Gemini™ PrepC18 10 μm column; Phenomenex, Torrance, Calif.; gradient elution of 20to 90% MeCN in water, where both solvents contain 0.1% TFA, a 15-mingradient in a 24-min method) to give, after lyophilization, 11 mg of(4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)-1-piperazinyl)aceticacid as a white solid. MS (ESI, +ve ion) m/z 769.7 (M+1)⁺.

Example 276(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

A solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aS)-8-(3-(phenylsulfonyl)propanoyl)octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-8-(3-(phenylsulfonyl)propanoyl)octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (15 mg, 0.016 mmol) and1,8-diazabicyclo-[5.4.0]undec-7-ene (0.15 mL, 1.0 mmol) in pyridine(0.30 mL) in a microwave reaction vessel was subjected to microwaveirradiation for 50 min at 75° C. The crude mixture was taken up in MeOHand subjected to preparative reverse-phase HPLC (Gemini™ Prep C₁₈ 10 μmcolumn; Phenomenex, Torrance, Calif.; gradient elution of 20 to 90% MeCNin water, where both solvents contain 0.1% TFA, a 15-min gradient in a24-min method) to give, after lyophilization, 7.5 mg of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE. MS (ESI, +ve ion) m/z 821.0 (M+1)⁺.

Example 345(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A solution of methyltriphenylphosphonium bromide (1.80 g, 5.0 mmol) inTHF (15 mL) was cooled to 0° C. n-butyllithium solution (2.5 M inhexanes, 1.8 mL, 4.5 mmol) was added dropwise and it was stirred at 0°C. for 10 min. The bromide solution was added dropwise to a solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (0.30 g, 0.50 mmol) in THF (6.0 mL) (cooled in ice bath)until the yellow color persisted. It was stirred at 0° C. for 12 min.The reaction mixture was added to stirred ice water (20 mL). It wasacidified with 1 N HCl to pH 2-4. The organic phase was separated andthe aqueous was extracted with EtOAc (50 mL). The organic phase waswashed with brine and dried over magnesium sulfate. The filtrate wasconcentrated to give crude product. The compound was purified by mediumpressure chromatography (silica, 0% to 50% EtOAc (+0.3% HOAc:Hexanes) togive(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (290 mg, 0.49 mmol, 97% yield). MS (ESI, +ve ion) m/z595.2 (M+H)⁺.

Step 2:(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

The AD-Mix-alpha mixture (640 mg, 0.43 mmol) was dissolved in a 20 mL ofa 1:1 mixture of tert-butanol (10.0 mL) and water (10.0 mL) and cooledto 0° C. The(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (255 mg, 0.428 mmol) was added and the reaction mixturewas warmed slowly to room temperature overnight. Another 5.0 mL oft-BuOH was added to homogenize the mixture. The reaction was stirredovernight. Another 320 mg of AD-Mix-alpha mixture was added and thereaction was stirred for an additional 3 d. The reaction was quenched byadding 575 mg of sodium sulfite at 0° C. and stirring for 45 minutes.The mixture was then extracted with EtOAc (2×25 mL). The combinedorganic layers were washed with brine (1×20 mL) and dried over sodiumsulfate. The crude product was then purified by medium pressurechromatography (silica, 0% to 100% EtOAc (+0.3% HOAc):heptanes) to give(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (31 mg, 0.049 mmol, 12% yield). MS (ESI, +ve ion) m/z629.2 (M+H)⁺.

Step 3:((1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methylmethanesulfonate

(1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (25.0 mg, 0.040 mmol) was dissolved in DCM (800 μL) andcooled to 0° C. Triethylamine (17 μL, 0.12 mmol) was added followed bymesyl chloride (6.50 μL, 0.083 mmol) addition and the reaction wasstirred for 1.5 h. The reaction was then diluted with DCM (15 mL) andthe mixture was washer with water (2×10 mL) and dried over sodiumsulfate. The crude product was then purified by medium pressurechromatography (silica, 0% to 70% EtOAc (+0.3% HOAc):heptanes) to give((1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methylmethanesulfonate. MS (ESI, +ve ion) m/z 707.2 (M+H)⁺.

Step 4:(1S,3′R,6′R,8′E,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

((1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methylmethanesulfonate (10 mg, 0.014 mmol) was dissolved in 0.36 mL of a 5:1DMF:water mixture. To the solution was added sodium azide (2.1 mg, 3.2μmol). The mixture was heated to 70° C. and stirred overnight. Thereaction was diluted with water and extracted with EtOAc. The organiclayer was dried over sodium sulfate and the crude product was purifiedby medium pressure chromatography (silica, 0% to 60% EtOAc (+0.3%HOAc):heptanes) to give(1S,3′R,6′R,8′E,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (2.1 mg, 3.2 μmol, 23% yield). MS (ESI, +ve ion) m/z654.2 (M+H)⁺.

Step 5:(1S,3′R,6′R,8′E,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

(1S,3′R,6′R,8′E,11′S,12′R)-7′-(Azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (2.0 mg, 3.1 μmol) was dissolved in2-methyltetrahydrofuran (1.0 mL) and sodium hydride (60% dispersion)(0.73 mg, 0.031 mmol) was added followed by methyl iodide (0.956 μL,0.015 mmol). The reaction was then stirred overnight to completion. Thereaction was quenched with dropwise addition of water and extracted withEtOAc. The organic layers were then washed with brine and dried overmagnesium sulfate to give(1S,3′R,6′R,8′E,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (3.0 mg) that was used directly in the next reactionwithout any further purification. MS (ESI, +ve ion) m/z 668.2 (M+H)⁺.

Step 6:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

(1S,3′R,6′R,8′E,11′S,12′R)-7′-(Azidomethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (20 mg, 0.030 mmol) was slurried in 3.0 mL of a 1:1:1t-BuOH:water:DMF solution. To the solution was added copper (II) sulfate(2.9 mg, 0.018 mmol), (+)-sodium 1-ascorbate (12.0 mg, 0.061 mmol) and(trimethylsilyl)acetylene (65 μL, 0.46 mmol). The solution was thenheated in a microwave reactor at 120° C. for 2 h. The reaction was thendiluted with water and EtOAc. The mixture was extracted with EtOAc (2×25mL). The combined organic layers were washed with 1 N lithium chloridesolution (1×15 mL) and brine (1×15 mL) then dried over magnesiumsulfate. The residue was then purified by medium pressure chromatography(silica, 25% to 100% EtOAc (+0.3% HOAc):heptanes) to give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide. MS (ESI, +ve ion) m/z 694.3 (M+H)⁺.

Example 348(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-(2-methylpropoxy)-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-11′,12′-dimethyl-7′-((2-methyl-2-propen-1-yl)oxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

The reaction was performed following the procedure for general method 5,step 2. MS (ESI, +ve ion) m/z 771.2 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-11′,12′-dimethyl-7′-(2-methylpropoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

The(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-11′,12′-dimethyl-7′-((2-methyl-2-propen-1-yl)oxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (200 mg, 0.26 mmol) was dissolved in EtOAc (5.0 mL) andplatinum (IV) oxide (180 mg, 0.78 mmol) was added. The vessel was thenpressurized to 40 psi with hydrogen and stirred for 3.5 h to completion.The black slurry was then filtered through a pad of Celite and washedwith EtOAc. The filtrate was then concentrated to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-11′,12′-dimethyl-7′-(2-methylpropoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (200 mg, 0.26 mmol, 100% yield). MS (ESI, +ve ion) m/z773.2 (M+H)⁺.

Step 3:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-(2-methylpropoxy)-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

The reaction was performed following the procedure for general method 5,step 3. MS (ESI, +ve ion) m/z 683.3 (M+H)⁺.

Step 4:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-(2-methylpropoxy)-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

The reaction was performed following the procedure for general method 8.MS (ESI, +ve ion) m/z 809.2 (M+H)⁺.

Examples 362 and 363(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2S)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2R)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)acetaldehyde(Example 360) (32 mg, 0.040 mmol) was dissolved in THF (2.0 mL) andcooled to 0° C. Methylmagnesium bromide (3.4 M in 2-MeTHF, 0.12 mL, 0.40mmol) was added dropwise and stirred for 45 min. The reaction wasquenched with saturated ammonium chloride solution (15 mL) and themixture was extracted with EtOAc (2×30 mL). The combined organic layerswere washed with brine (1×20 mL) and then dried over sodium sulfate. Themixture was then purified by preparatory SCF chromatography (4FBSA, 250mm×21 mm column, Phenomenex, Torrance, Calif.; 28 g/minute MeOH (+20 mMNH₃)+42 g/minute CO₂ on Thar 200 SFC; outlet pressure=100 bar;temperature=40° C.; wavelength=220 nm; used 1.1 mL injections of 28 mg/3mL (9.3 mg/mL) sample solution of MeOH (3 mL) to give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2S)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2R)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 362, first eluting isomer, t_(R)=3.19 minuteson analytical SFC; 4FBSA; 40% MeOH (+20 mM NH₃ in CO₂) with >99.5% de)(6.2 mg, 7.7 μmol, 19% yield). MS (ESI, +ve ion) m/z 809.4 (M+H)⁺. And(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2S)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2R)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 363, second eluting isomer, t_(R)=6.49 minuteson analytical SFC; 4FBSA; 40% MeOH (+20 mM NH₃ in CO₂) with >99.5% de)(13 mg, 0.016 mmol, 39% yield). MS (ESI, +ve ion) m/z 809.4 (M+H)⁺.

Examples 364 and 366(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,16′H-spiro[naphthalene-1,23′-[21]oxa[27]thia[1,15]diazapentacyclo[15.7.2.1˜12,15˜.0-3,6˜.0˜20,25˜]heptacosa[8,17,19,25]tetraen]-16′-one27′,27′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-chloroethyl)-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethylmethanesulfonate

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-Chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 346) (15 mg, 0.018 mmol) was dissolved in DCM(1.0 mL) and the Hunig's base (0.011 mL, 0.064 mmol) and mesyl chloride(3.7 μL, 0.048 mmol) were added. The reaction mixture was stirred for1.5 h to near completion. The mixture was then diluted with DCM (20 mL)and water (15 mL). The layers were separated and the organic layer wasdried over sodium sulfate. The filtrate was concentrated to drynessunder vacuum to give2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethylmethanesulfonate (16 mg, 0.018 mmol, 100% yield) that was used directlyin the next reaction. MS (ESI, +ve ion) m/z 875.3 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,16′H-spiro[naphthalene-1,23′-[21]oxa[27]thia[1,15]diazapentacyclo[15.7.2.1˜12,15˜.0˜3,6˜.0˜20,25˜]heptacosa[8,17,19,25]tetraen]-16′-one27′,27′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-chloroethyl)-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-Chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethylmethanesulfonate (16 mg, 0.018 mmol) was dissolved in acetonitrile (1.0mL) and tetrabutylammonium difluoro-triphenylsilicate (59 mg, 0.11 mmol)was added. The reaction was then heated at 75° C. to completion. Thereaction was then cooled to room temperature and then diluted with EtOAc(25 mL) and water (20 mL). The layers were separated and the organiclayer was washed again with water (1×20 mL) and brine (1×20 mL) anddried over sodium sulfate. The crude product was then purified by mediumpressure chromatography (silica, 0% to 100% (10% 2 M ammonia inMeOH):DCM) to give two products,(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,16′H-spiro[naphthalene-1,23′-[21]oxa[27]thia[1,15]diazapentacyclo[15.7.2.1-12,15˜.0˜3,6˜.0˜20,25˜]heptacosa[8,17,19,25]tetraen]-16′-one27′,27′-dioxide (Example 364) (4.9 mg, 6.3 μmol, 34% yield), MS (ESI,+ve ion) m/z 779.3 (M+H)⁺ AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-chloroethyl)-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 366) (3.5 mg, 4.29 μmol, 23% yield), MS (ESI,+ve ion) m/z 815.3 (M+H)⁺.

Examples 358, 359, and 367(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 358) and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 359) and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-(dimethylamino)ethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 367)

Step 1:(3R,4S)-1-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL-6-HEPTENE-3-SULFONAMIDE

To a solution of(S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (2.8 g,6.9 mmol) in THF (15 mL) was added n-butyllithium (2.5 M in hexanes, 3.1mL, 7.6 mmol) at −78° C. dropwise. The mixture was stirred at −78° C.for 5 min, and ethylene oxide (2.5 M in THF, 5.6 mL, 14 mmol) was thenadded. The mixture was allowed to warm up to ambient temperature andstirred for 18 h. The mixture was quenched with saturated aqueous NH₄Cl,and extracted with EtOAc (2×). The organic layer was washed with brine,dried (MgSO₄), and filtered. The filtrate was concentrated and theresulting residue was chromatographed (silica gel, 20% to 60%,EtOAc/Hexane) to afford a diasteromeric mixture of the title compound.The mixture was then purified by preparatory SFC chromatography(ChiralPak IC-H 250 mm×30 mm column, Phenomenex, Torrance, Calif.; 35g/minute MeOH+105 g/minute CO₂ on Thar 200 SFC; outlet pressure=100 bar;temperature=22° C.; wavelength=215 nm; used 1.0 mL injections of 25,000mg/50 mL (500 mg/mL) sample solution of MeOH (50 mL) to provide(3R,4S)-1-hydroxy-N,N-bis(4-methoxybenzyl)-4-methyl-6-heptene-3-sulfonamideas the slower eluting isomer as a yellow liquid (t_(R)=2.51 minutes onanalytical SFC; IC-H column; 25% MeOH in CO₂) with 100% de. ¹H NMR (400MHz, DICHLOROMETHANE-d₂) δ ppm 7.24 (d, J=8.61 Hz, 4H), 6.90 (d, J=8.61Hz, 4H), 5.62 (ddt, J=16.75, 10.20, 7.07, 7.07 Hz, 1H), 5.08 (s, 1H),5.05 (br d, J=7.83 Hz, 1H), 4.39 (d, J=15.26 Hz, 2H), 4.23 (d, J=15.26Hz, 2H), 3.83 (s, 6H), 3.66-3.81 (m, 2H), 3.00-3.16 (m, 1H), 1.97-2.23(m, 3H), 1.79-1.96 (m, 3H), 1.06 (d, J=6.85 Hz, 3H). MS (ESI, +ve ion)m/z 470.2 (M+Na)⁺.

Step 2:(3R,4S)—N,N-bis(4-methoxybenzyl)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide

(3R,4S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide(6.4 g, 14 mmol) was dissolved in DMF (34 mL). Imidazole (1.7 g, 24mmol) and tert-butyldiphenylsilyl chloride (6.3 mL, 24 mmol) were addedand the mixture was stirred for 45 min. The reaction was then quenchedwith saturated ammonium chloride solution (150 mL) and extracted withEtOAc (1×300 mL). The layers were separated and the organic was washed(1×100 mL) with 1 N LiCl solution (1×100 mL), 1 N HCl solution and(1×100 mL) of brine and then dried over magnesium sulfate. The crudeproduct was then purified by medium pressure chromatography (silica, 5%to 100% EtOAc:Heptanes) to give(3R,4S)—N,N-bis(4-methoxybenzyl)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide(9.70 g, 14.14 mmol, 98% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.67(dt, J=1.5, 7.3 Hz, 4H), 7.47-7.35 (m, 6H), 7.16 (d, J=8.8 Hz, 4H),6.79-6.78 (m, 1H), 6.81 (d, J=8.6 Hz, 3H), 5.56 (tdd, J=7.0, 10.1, 17.0Hz, 1H), 4.97 (dd, J=1.8, 10.0 Hz, 1H), 4.91 (dd, J=1.6, 17.0 Hz, 1H),4.31-4.10 (m, 4H), 3.84-3.80 (m, 1H), 3.78 (s, 6H), 3.77-3.72 (m, 1H),3.09 (ddd, J=1.6, 4.2, 7.4 Hz, 1H), 2.22-2.07 (m, 2H), 1.98-1.79 (m,3H), 1.07 (s, 9H), 1.02 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 708.3(M+Na)⁺.

Step 3:(3R,4S)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide

To a 1000 mL flask cooled to 0° C., was added(3R,4S)—N,N-bis(4-methoxybenzyl)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide(9.4 g, 14 mmol), DCM (290 mL), anisole (7.5 mL, 69 mmol) and thentrifluoroacetic acid (49 mL). The reaction was allowed to warm to roomtemperature overnight to completion. The reaction mixture was thenconcentrated on the rotovap to a volume of −25 mL. The crude product wasthen purified by medium pressure chromatography (silica, 10% to 50%EtOAc:heptanes) to give(3R,4S)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide(2.7 g, 6.1 mmol, 44% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.67(ddd, J=1.5, 5.8, 7.2 Hz, 4H), 7.49-7.37 (m, 6H), 5.72 (tdd, J=6.9,10.1, 17.0 Hz, 1H), 5.06-4.94 (m, 2H), 4.41 (br s, 2H), 3.93-3.80 (m,2H), 3.23-3.16 (m, 1H), 2.46 (m, 1H), 2.13-2.06 (m, 1H), 2.05-2.01 (m,1H), 1.91 (dtd, J=3.7, 7.1, 14.7 Hz, 2H), 1.07 (s, 9H), 1.02 (d, J=7.0Hz, 3H). MS (ESI, +ve ion) m/z 468.2 (M+Na)⁺.

Step 4:(3S)-6′-chloro-5-(((1R,2R)-2-((1S)-1-hydroxy-2-propen-1-yl)cyclobutyl)methyl)-N-(((3R,4S)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-hepten-3-yl)sulfonyl)-3′,4,4′,5-tetrahydro-2′H-spiro[1,5-benzoxazepine-3,1′-naphthalene]-7-carboxamide

The reaction was performed following the procedure for general method 1(R¹=H). MS (ESI, +ve ion) m/z 895.3 (M+H)⁺.

Step 5:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

The reaction was performed following the procedure for general method 1(R¹=H). MS (ESI, +ve ion) m/z 867.3 (M+H)⁺.

Step 6:(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide

The reaction was performed following the procedure for general method 1(R¹=H). MS (ESI, +ve ion) m/z 865.3 (M+H)⁺.

Step 7:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

The reaction was performed following the procedure for general method 3(R⁴=Me). MS (ESI, +ve ion) m/z 911.4 (M+H)⁺.

Step 8:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

The reaction was performed following the procedure for general method 3(R⁴=Me). MS (ESI, +ve ion) m/z 909.3 (M+H)⁺.

Step 9:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 359)

The reaction was performed following the procedure for general method 8.MS (ESI, +ve ion) m/z 1033.3 (M+H)⁺.

Step 10:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 358)

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 359) (38 mg, 0.037 mmol) was dissolved in THF(1.0 mL). Tetrabutylammonium fluoride (1.0 M in THF, 1.1 mL, 1.1 mmol)was then added and the reaction was stirred for 24 h to completion. Thereaction mixture was then diluted with DCM and then loaded directly on acolumn to purify by medium pressure chromatography (silica, 0% to 100%(hold) (10% 2 M ammonia in MeOH:DCM):DCM) to give product that wascontaminated with tetrabutylammonium fluoride. This material was thendiluted with water (50 mL) and EtOAc (20 mL). The layers were thenseparated and the organic layer was then washed again with water (1×50mL) to remove the residual tetrabutylammonium fluoride. The organiclayer was then extracted with brine (1×15 mL) and dried over sodiumsulfate. The slurry was filtered and the filtrate was concentrated togive(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 358) (150 mg, 0.18 mmol, 61% yield). MS (ESI,+ve ion) m/z 795.3 (M+H)⁺.

Step 11:2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethylmethanesulfonate

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 358) (50 mg, 0.063 mmol) was dissolved in DCM(3.0 mL) and the Hunig's Base (66 μL, 0.38 mmol) and mesyl chloride (21μL, 0.26 mmol) were added. The reaction mixture was stirred for 1.5 h tocompletion. The mixture was then diluted with DCM (20 mL) and water (25mL). The layers were separated and the organic layer was washed againwith water (25 mL) and then was dried over sodium sulfate. The filtratewas concentrated to dryness under vacuum to give2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethylmethanesulfonate (63 mg). MS (ESI, +ve ion) m/z 873.3 (M+H)⁺.

Step 12:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-(dimethylamino)ethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 367)

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethylmethanesulfonate (30 mg, 0.34 mmol), dimethylamine (2 M in THF, 0.17 mL,0.34 mmol), potassium carbonate (95 mg, 0.69 mmol) and a catalyticamount of potassium iodide was dissolved in acetonitrile (1.0 mL) in avial and sealed with a pressure cap. The reaction mixture was thenheated to 65° C. for 40 min to completion. The reaction was then dilutedwith DCM and filtered through a fine glass frit. The filtrate was thenconcentrated and the residue was then purified by preparatory SFCchromatography (Kromasil Cyano 250 mm×21 mm column 17.5 g/minute MeOH(+20 mM ammonia)+52.5 g/minute CO₂ on Thar 200 SFC; outlet pressure=100bar; temperature=22° C.; wavelength=215 nm; used 1.0 mL injections of 31mg/4 mL (7.8 mg/mL) sample solution of MeOH (4 mL) to give(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-(dimethylamino)ethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 367) (4.7 mg, 5.7 mmol, 17% yield) as theslower eluting peak (t_(R)=2.90 minutes on analytical SFC; KromasilCyano column 25% MeOH in CO₂) with 97.8% purity. MS (ESI, +ve ion) m/z822.3 (M+H)⁺.

Examples 399 and 400(1S,3′R,6′R,7′R,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,9a′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide

A glass microwave reaction vessel was charged with(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-oxiran]-15′-one13′,13′-dioxide (0.300 g, 0.489 mmol) and 3(R)-hydroxymethylmorpholine(0.650 g, 5.55 mmol; Matrix Sci., Elgin, S.C.). Ethanol (3 mL) andtriethylamine (1.8 mL, 12.9 mmol) were added, the reaction mixture wassealed under argon, and heated in an Initiator microwave reactor at 90°C. for a total of 27 h. The reaction was heated at 90° C. in themicrowave for another 16 h. The reaction mixture was purified byreverse-phase HPLC (Gilson; Gemini-NX 10 μm, C18, AXIA, 100×50 mmcolumn) eluting with 0.1% TFA-H₂O:0.1% TFA CH₃CN (9:1→1:9). Thefractions containing the desired product were combined and partitionedbetween pH 7 buffer (1 M K₂HPO₄/KH₂PO₄)/EtOAc. The aqueous layer wasextracted with EtOAc (3×) and the combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under reduced pressure to give a mixture of(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (177 mg, 50%) as a white crystalline solid.

Step 2:(1S,3′R,6′R,7′R,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide

To a room temperature mixture of(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (0.136 g, 0.186 mmol) in tetrahydrofuran (4 mL) wasadded sodium hydride, 60% dispersion in mineral oil (0.050 g, 1.250mmol) and the reaction was stirred for 30 min. To the reaction was addedp-toluenesulfonic anhydride (0.250 g, 0.766 mmol) and the reaction wasstirred for 5.5 h. To the reaction was added sodium hydride, 60%dispersion in mineral oil (0.050 g, 1.250 mmol) and the reaction wasstirred overnight. To the reaction was added p-toluenesulfonic anhydride(0.180 g) and the reaction was stirred for 24 h. To the reaction wasadded sodium hydride, 60% dispersion in mineral oil (0.050 g, 1.25 mmol)and the reaction was stirred for another 24 h. The reaction was quenchedwith pH 7 buffer (1 M K₂HPO₄/KH₂PO₄) and the aqueous layer was extractedwith EtOAc (3×). The combined organic layers were washed with brine andthe filtrate was purified by reverse-phase HPLC (Gilson; Gemini-NX 10μm, C₁₈, AXIA, 100×50 mm column) eluting with 0.1% TFA-H₂O:0.1% TFACH₃CN (9:1→1:9). The fractions containing the desired product werecombined and partitioned between pH 7 buffer (1 M K₂HPO₄/KH₂PO₄)/EtOAc.The aqueous layer was extracted with EtOAc (3×) and the combined organiclayers were washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure to give 118 mg (89%) ofa white solid. The material was purified by achiral SFC chromatographyto give(1S,3′R,6′R,7′R,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′S,9a′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide (10 mg, 8%, first eluted peak) as a white crystallinesolid. m/z (ESI, +ve ion) 712.7 (M+1)⁺. A second eluting compound wasisolated as(1S,3′R,6′R,7′R,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′S,9a′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one13′,13′-dioxide (12 mg, 9%, second eluted peak) as a white crystallinesolid. (ESI, +ve ion) m/z 712.6 (M+1)⁺.

Example 405(1S,3′R,6′R,7′S,10′S,11′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-10′,11′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide

A vial was charged with(1S,3′R,6′R,7′S,8′E,10′S,11′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-10′,11′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.012 g, 0.016 mmol) and platinum (IV) oxide (0.4 mg,1.6 μmol). Ethanol (2 mL) and methanol (0.3 mL) were added. The reactionwas flushed with nitrogen for 5 min then evacuated/backfilled withhydrogen three times. The reaction was stirred under 20 psi hydrogen atroom temperature overnight. The reaction was flushed with nitrogen.Methanol (5 mL) and DCM (5 mL) were added. The reaction was flushed withnitrogen then evacuated/backfilled with hydrogen three times. Thereaction was stirred under 20 psi hydrogen at room temperature for 24 h.The reaction was flushed with nitrogen and filtered through celiterinsing with ethyl acetate. The filtrate was concentrated under reducedpressure and purified by silica gel flash chromatography using agradient of 0% to 10% MeOH in DCM to afford the title compound (0.007 g,9 μmol, 58% yield). MS (ESI, +ve ion) m/z 755.2 (M+H)⁺.

Example 466(1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-11′,12′-DIMETHYL-4′-(METHYLSULFONYL)-3,4-DIHYDRO-2H,15′H-DISPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIENE-7′,2″-[1,4]OXAZINAN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-11′,12′-DIMETHYL-4″-(METHYLSULFONYL)-3,4-DIHYDRO-2H,15′H-DISPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIENE-7′,2″-[1,4]OXAZINAN]-15′-ONE13′,13′-DIOXIDE

To a stirred solution of(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (Example 452) (34 mg, 0.043 mmol) in THF (1.5 mL) in amicrowave reaction vessel was added at room temperature,diisopropylethylamine (0.075 mL, 0.431 mmol) under argon followed bymethanesulfonic anhydride (37.6 mg, 0.216 mmol). The resulting mixturewas stirred at room temperature for 5 min during which the color of themixture changed from colorless to light greenish yellow. The vessel wascapped and subjected to microwave reaction irradiation (3 h at 70° C.).4-(Dimethylamino)pyridine (15.81 mg, 0.129 mmol) was then added followedby more methanesulfonic anhydride (18 mg, 0.11 mmol). The vessel wassealed and again subjected to microwave irradiation (4 h at 70° C.). Thevolatiles were removed and the concentrate was dissolved in DMSO andpurified by preparative reverse-phase HPLC (Gemini™ Prep C18 5 μmcolumn; Phenomenex, Torrance, Calif.; gradient elution of 30% to 95%MeCN in water, where both solvents contain 0.1% TFA, 25 min method) toprovide, after lyophilization, 4.0 mg of(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-4″-(methylsulfonyl)-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-4″-(methylsulfonyl)-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-[1,4]oxazinan]-15′-one13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 734.2 (M+1)⁺.

Examples 499 and 500 METHYL3-((9AR)-8-(((1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATEAND METHYL3-((9AR)-8-(((1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATEAND METHYL3-((9AS)-8-(((1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATEAND METHYL3-((9AS)-8-(((1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE(Example 499) AND(1S,3′R,6′R,7′R,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′R,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′S,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′S,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE (Example 500)

To a stirred solution of(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrazino[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aS)-octahydro-2H-pyrazino[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrazino[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aS)-octahydro-2H-pyrazino[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (Example 479) (0.15 g, 0.199 mmol) anddiisopropylethylamine (1.5 mL, 8.62 mmol) in DCM (10 mL) was added atroom temperature acrylic acid n-hydroxysuccinimide ester (0.303 g, 1.789mmol) in one portion as a solid. The resulting mixture was stirred atroom temperature for 3 h. MeOH (8 mL) was added to the reaction mixture.The resulting mixture was stirred at room temperature for 20 min beforeconcentrated in vacuo. The crude residue was directly loaded onto asilica gel precolumn (25 g) and subjected to combi-flash columnchromatography on a 12 g ISCO gold column eluting with 1% to 20%MeOH/DCM to give 30 mg of impure product mixture, which was subjected topreparative reverse-phase HPLC (Gemini™ Prep C18 10 m column;Phenomenex, Torrance, Calif.; gradient elution of 20% to 90% MeCN inwater, where both solvents contain 0.1% TFA, a 15-min gradient in a24-min method) to give, after lyophilization, 18.5 mg of METHYL3-((9AR)-8-(((1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATEAND METHYL3-((9AR)-8-(((1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATEAND METHYL3-((9AS)-8-(((1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATEAND METHYL3-((9AS)-8-(((1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE(EXAMPLE 499) in an approximately 1-to-1-to-1-to-1 epimeric mixture. MS(ESI, +ve ion) m/z 841.0 (M+1)⁺. In addition,(1S,3′R,6′R,7′R,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′R,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′S,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE AND(1S,3′R,6′R,7′S,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE (EXAMPLE 500) was isolated as a white solid in a1-to-1-to-1-to-1 epimeric mixture. MS (ESI, +ve ion) m/z 808.8 (M+1)⁺.

Example 507(1S,3′R,6′R,7′S,11′S,12′R)-7′-(aminomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′S,11′S,12′R)-7′-(aminomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide

(1S,3′R,6′R,7′S,11′S,12′R)-7′-(Azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6.0˜19,24]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6.0˜19,24]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (Example 506) (36.0 mg, 0.055 mmol) was dissolved inethyl acetate (5.0 mL) and platinum(IV) oxide (2.49 mg, 11.0 μmol) wasadded. The reaction vessel was filled with hydrogen to 15 psi andstirred vigorously for 2.5 h. MeOH (1.5 mL) was added and the reactionvessel was again filled with hydrogen (15 psi) and stirred overnight.The slurry was filtered and the precipitate was washed with DMSO toensure that no product was remaining on the catalyst. The filtrate wasconcentrated. The crude material was purified by reverse-phasepreparative HPLC using a Phenomenex Gemini column, 10 μm, C18, 100 Å,150×30 mm, 0.1% TFA in CH₃CN/H₂O, gradient 20% to 85% over 30 min toprovide(1S,3′R,6′R,7′S,11′S,12′R)-7′-(aminomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-7′-(aminomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (32 mg, 0.037 mmol, 68% yield) as a di-TFA salt. MS(ESI, +ve ion) m/z 630.2 (M+H)⁺.

Examples 517 and 518(1S,3′R,6′R,7′R,11′S,12′R)-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide

A reaction vessel was charged with platinum (IV) oxide (18.6 mg, 0.082mmol), then placed in a Biotage Endeavor and treated with a solution of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,l-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (128 mg) in EtOAc (3 mL). The vessel was purged with Ar(3×), then pressurized to 200 psi with H₂ and stirred (250 RPM) at 80°C. for 20 h. The vessel was cooled to room temperature and purged withAr (3×), then filtered through a celite pad that was rinsed liberallywith EtOAc. The filtrate was concentrated in vacuo and purified byreverse-phase preparative HPLC (Shimadzu) on a Phenomenex Luna column (5m, C18, 110 Å, Axia, 150 mm×21.2 mm) eluting at 30 mL/min with a lineargradient of 25% to 100% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min.The desired fractions were poured into 10% Na₂CO₃ and extracted with DCM(2×5 mL). The combined organic layers were dried over MgSO₄ andconcentrated in vacuo to afford(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (Example 518) (32.8 mg, 0.040 mmol, 13% yield) as awhite solid. MS (ESI, +ve ion) m/z 827.2 (M+H)⁺. In addition,(1S,3′R,6′R,7′R,11′S,12′R)-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (Example 517) was isolated as an earlier eluting peak(12.9 mg, 0.016 mmol, 6% yield) as a white solid. MS (ESI, +ve ion) m/z793.3 (M+H)⁺.

Example 519(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(2-propanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide

A reaction vessel was charged with sulfided Pt on carbon (5% wt %, 54.2mg, 0.295 mmol), then placed in the Biotage Endeavor and treated with asolution of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide [derived from methods analogous to General Method 3,steps 1-2 using(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide](207 mg, 0.295 mmol) in EtOAc (3.25 mL). The vessel waspurged with Ar (3×), then pressurized to 200 psi with H₂ and stirred(250 RPM) at 80° C. for 20 h. The vessel was cooled to room temperatureand purged with Ar (3×), then filtered through a celite pad that wasrinsed liberally with EtOAc. The filtrate was concentrated in vacuo toafford(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (196 mg, 0.279 mmol, 94% yield) as a white solid. MS(ESI, +ve ion) m/z 703.3 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′-carbaldehyde13′,13′-dioxide

To an ice bath cooled solution of(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (161 mg, 0.229 mmol) in DCM (10 mL) was added 0.3 MDess-Martin Periodinane in DCM (1.0 mL, 0.300 mmol) dropwise over 2 min.After 1.5 h, LC-MS suggests about 60% conversion, the reaction wastreated with another 0.9 mL of 0.3 M Dess-Martin Periodinane in DCMdropwise over 1 min. After a further 2.5 h, LC-MS suggests completeconversion. The reaction was treated with 5 mL of saturated sodiumbisulfite and stirred for 20 min. The reaction was poured into water (15mL) and the organic layer separated. The aqeuous layer was extractedwith DCM (1×5 mL). The combined organic layers were concentrated invacuo and adsorbed onto a plug of silica gel and chromatographed througha Redi-Sep® pre-packed silica gel column (Gold, 12 g), eluting with 0%to 25% EtOAc in heptanes, to afford(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′-carbaldehyde13′,13′-dioxide (105 mg, 0.150 mmol, 65.4% yield) as a white solid. MS(ESI, +ve ion) m/z 701.2 (M+H)⁺.

Step 3:(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(2-propanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide

To a round bottom flask was charged the TFA salt of(R)-1-isopropyl-2-methylpiperazine (68.2 mg, 0.285 mmol) and(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′-carbaldehyde13′,13′-dioxide (50 mg, 0.071 mmol) in DCE (2 mL) andN,N-diisopropylethylamine (0.1 mL, 0.574 mmol). After 1.5 h, thesolution was treated with sodium triacetoxyborohydride (6 mg). After afurther 3 h, the reaction was treated with more sodiumtriacetoxyborohydride (7 mg). After a further 16 h, the reaction wasagain treated with sodium triacetoxy borohydride (6 mg). The reactionwas monitored by LC-MS and sodium triacetoxyborohydride added in 5-10 mgportions until reaction was judged complete. After a further 24 h, thereaction was diluted with DCE (3 mL). After 4 d, the reaction wastreated with acetic acid (12 μL, 0.208 mmol). After a further 24 h, moreacetic acid (18 μL) was added. After a further 24 h, the reaction wastreated with another 30 mg of amine. After a further 96 h, the reactionwas treated with larger portions of sodium triacetoxyborohydride todrive reaction to desired product or the alcohol resulting from reducedaldehyde. LC-MS suggests no further progress, the reaction was quenchedwith water and the aqeuous layer extracted with DCM (2×10 mL). Thecombined DCM layers were concentrated in vacuo and adsorbed onto a plugof silica gel and chromatographed through a Redi-Sep® pre-packed silicagel column (Gold, 12 g), eluting with 0% to 80% EtOAc:EtOH (3:1) inheptanes, to afford(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(2-propanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (24.2 mg, 0.029 mmol, 41.0% yield) as a white solid. MS(ESI, +ve ion) m/z 827.4 (M+H)⁺.

Table 1 lists compounds prepared by the General Methods outlined in thepresent specification.

TABLE 1 Examples Prepared by the General Methods MS Example StartingGeneral Data Number Materials Method Product Structure Product Name (M +1)⁺ 22

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2.1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13-dioxide 812.4 23

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′- methyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25] triazatetracyclol[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 812.224

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′- methyl-7′-((4-(1- methylethyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 798.225

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-7′- ((4-(2-methoxy-l- (methoxymethyl)ethyl)-1-piperazinyl)methyl)-11′- methy1-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 858.4 26

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′- methyl-7′-((4-((5-methyl- 1,2,4-oxadiazol-3-yl)methyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 852.4 27

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-7′-((4-(2-methoxy-1,1- dimethylethyl)-1- piperazinyl)methyl)-12′-(2-methoxyethyl)-11′-methyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 842.428

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-12′-ethyl-7′- ((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.2

29

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-12′-ethyl-7′-methoxy-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 765.2

30

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-12′-ethyl-7′- ((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.2

31

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′S,8′E,12′R)- 6-chloro-12′-ethyl-7′-methoxy-7′-((4-methyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 725.2

32

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′R,8′E,12′R)- 6-chloro-12′-ethyl-7′- methoxy-7′-((9aR)-octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 765.2

35

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((methyl(2-(4- morpholinyl)ethyl)amino)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 769.236

5, 13

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((2-(4- morpholinyl)ethyl)amino) methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 755.2 37

5, 13

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((methyl(2-(4- morpholinyl)ethyl)amino) methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 769.2 38

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-12′-(cyclobutylmethyl)-7′-((9aS)- hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 821.2

39

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-12′-(cyclobutylmethyl)-7′-((9aS)- hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 821.2

40

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-12′- (cyclobutylmethyl)-7′-methoxy-11′-methyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 819.2

41

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-12′- (cyclobutylmethyl)-7′-methoxy-11′-methyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 819.2

42

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′R,8′E,12′R)- 6-chloro-7′-ethoxy-12′-ethyl-7′-((9aR)-octahydro- 2H-pyrido[1,2,a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 779.2

43

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′S,8′E,12′R)- 6-chloro-7′-ethoxy-12′-ethyl-7′-((9aR)-octahydro- 2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 779.2

44

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-12′- (cyclobutylmethyl)-7′-ethoxy-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylmethyl)-11′-methyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 835.2

45

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-12′- (cyclobutylmethyl)-7′-ethoxy-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylmethyl)-11′-methyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 835.2

46

3, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-7′-(2-propen-1- yloxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 793.2 47

3, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-7′-(1- methylethoxy)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 795.2 48

3, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-butoxy-6-chloro- 7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 809.249

3, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-7′-(2,2,2- trifluoroethoxy)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 835.2 50

3, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-7′-(2,2,2- trifluoroethoxy)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 835.2 51

3, 10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′-12′- dimethyl-7′-(1-methylethoxy)-7′-(((3R)-3- methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 795.252

5, 12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 712.2

53

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(4-morpholinylmethyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 712.3

54

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((4-(2-methoxyethyl)-3-oxo-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 783.2 55

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy7′-((4-(2-methoxyethyl)-3- oxo-1-piperazinyl)methyl)-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 783.256

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 767.357

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 767.358

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 767.359

5, 10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((3-(dimethylamino)-3-methyl- 1-azatidinyl)methyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 739.460

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((3-(dimethylamino)-3-methyl- 1-azatidinyl)methyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 739.361

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((4-(2-methoxyethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 769.4 62

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-methyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 725.5 63

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((8aS)-3- oxotetrahydro[1,3]oxazolo[3,4-a]pyrazin-7(1H)- yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.3 64

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((8aS)-3- oxotetrahydro[1,3]oxazolo[3,4-a]pyrazin-7(1H)- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.3 65

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((methylamino)methyl)- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 656.4 66

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- ((dimethylamino)methyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 670.3 67

5, 10

1-(((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)- 3-methyl-3- azetidinecarbonitrile 721.3 68

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((5-fluoro-3,6-dihydro-1(2H)- pyridinyl)methyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 726.369

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- ((dimethylamino)methyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 670.2 70

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((methylamino)methyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 656.271

10

1-(((1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)- 3-methyl-3- azetidinecarbonitrile 721.3 72

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-(1,3-thiazol-4- ylmethyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 808.2 73

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-(2- methylsulfonyl)ethyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 817.2 74

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-piperidinylmethyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 710.375

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-piperidinylmethyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 710.276

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(1- azetidinylmethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 682.3 77

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(1- azetidinylmethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 682.3 78

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((9aS)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 765.879

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((9aS)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 765.880

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((8aR)-hexahydropyrrolo[1,2- a]pyrazin-2(1H)-ylmethyl)- 7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((8aS)-hexahydropyrrolo[1,2- a]pyrazin-2(1H)-ylmethyl)- 7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′- 751.8

[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 81

5, 9

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(2- (methylsulfonyl)ethyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 818.082

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((3aR,6aS)-5- methylhexahydropyrrolo[3, 4-c]pyrrol-2(1H)-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 751.283

9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((8aR)-hexahydropyrrolo[1,2- a]pyrazin-2(1H)-ylmethyl)- 7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one13′,13′-dioxide|(1S,3′R,6′R, 7′R,8′E,11′S,12′R)-6-chloro-7′-((8aS)-hexahydropyrrolo[1, 2-a]pyrazin-2(1H)-ylmethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H, 751.2

15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 84

9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((3-(4-morpholinyl)-1- azetidinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.2 85

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-(4-morpholinyl)-1- piperidinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide795.9 86

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((4aR,8aS)-octahydro-2(1H)-isoquinolinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((4aS,8aR)-octahydro-2(1H)-isoquinolinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] 764.8

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 87

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((10aR)- octahydropyrazino[1,2-a]azepin-2(1H)-ylmethyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((10aS)- octahydropyrazino[1,2-a]azepin-2(1H)-ylmethyl)- 3,4-dihydro-2H,15′H- 779.8

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 88

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4-ethyl-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide739.8 89

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4aR,8aS)-octahydro- 2(1H)-isoquinolinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4aS,8aR)-octahydro-2(1H)-isoquinolinylmethyl)- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] 764.2

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 90

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4aS,8aR)-octahydro- 2(1H)-isoquinolinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R.6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4aR,8aS)-octahydro-2(1H)-isoquinolinylmethyl)- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] 764.2

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 91

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4- cyclopropyl-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide751.8 92

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4- cyclobutyl-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide765.8 93

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-(2,2,2-trifluoroethyl)- 1-piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 794.0 94

9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((3-((2-methoxyethyl)(methyl)amino)- 1-azetidinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 769.8 95

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4-(2,2- difluoroethyl)-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide775.8 96

9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4-(2- fluoroethyl)-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide757.2 97

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-propyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide753.3 98

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-((4- propyl-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.3 101

5, 9

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 781.8 102

1, 5, 9

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-12′-benzyl-6-chloro- 7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-12′-benzyl-6-chloro- 7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide844.0 103

1, 5, 9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-12′-benzyl-6-chloro- 7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-12′-benzyl-6-chloro- 7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- 844.0

[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 104

1, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-12′-benzyl-6-chloro-7′-methoxy-11′-methyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-12′-benzyl-6-chloro-7′-methoxy-11′-methyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~ 841.2

3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 106

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 781.2 107

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 779.3

108

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 779.3

109

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-(2- oxa-7-azaspiro[3.5]non-7-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide766.3

110

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4- (dimethylamino)-1-piperidinyl)methyl)-7′- ethoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide767.3

111

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((4-(2-methoxy-1-(methoxymethyl)ethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 827.2 112

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((4-ethyl-1-piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide753.3 113

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((methoxy-1-piperidinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide754.8 114

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-((4-(1- methylethyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.3

115

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-((4-(1- methylethyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.8

116

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((4-(2-methoxy-1-(methoxymethyl)ethyl)- piperazinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 828.0 117

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-methoxy-1-piperidinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide740.7 118

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4- (dimethylamino)-1-piperidinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide753.7 119

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-(1- oxa-7-azaspiro[3.5]non-7-ylethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide766.8 120

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1- oxa-7-azaspiro[3.5]non-7-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide752.8 121

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-ethoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-ethoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] 830.0

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 122

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-ethoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-ethoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] 830.0

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 123

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy-7′-((4-(2-methoxyethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 783.9 129

See Example 138 (Step 1)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- hydroxy-7′-(((2-hydroxyethyl)(methyl)amino) methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 686.3 130

See Example 138 (Step 2)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-4″,11′,12′-trimethyl-3,4-dihydro- 2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one- 13′,13′-dioxide 668.3 131

See Example 138 (Step 1 with Net₃ due to HCl salt, Step 2)

(1S,3′R,6′R,7′R,8′E,9a″R, 11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4,6″,7″,9″,9a″- hexahydro-1″,2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraene-7′,3″- [1,4]oxazino[3,4-c[1,4]oxazin]-15′-one- 13′,13′-dioxide 710.2 132

See Example 138 (Steps 1- 2)

(1S,3′R,6′R,7′R,8′E,9a″R, 11′S,12′R)-6-chloro- 8″,11′,12′-trimethyl-1″,3,4,6″,7″,8″,9″,9a″- octahydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraene-7′,3″- pyrazino[2,1-c][1,4]oxazin]-15′-one- 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,9a″S,11′S,12′R)-6-chloro- 8″,11′,12′-trimethyl- 1″,3,4,6″,7″,8″,9″,9a″-octahydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 723.3

3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraene-7′,3″- pyrazino[2,1-c][1,4]oxazin]-15′-one- 13′,13′-dioxide 133

See Example 138 (Steps 1- 2)

(1S,3′R,6′R,7′R,8′E,9a″R, 11′S,12′R)-6-chloro- 8″,11′,12′-trimethyl-1″,3,4,6″,7″,8″,9″,9a″- octahydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraene-7′,3″- pyrazino[2,1-c][1,4]oxazin]-15′-one- 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,9a″S,11′S,12′R)-6-chloro- 8″,11′,12′-trimethyl- 1″,3,4,6″,7″,8″,9″,9a″-octahydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 723.3

3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraene-7′,3″- pyrazino[2,1-c][1,4]oxazin]-15′-one- 13′,13′-dioxide 134

See Example 138 (Steps 1- 2)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraene-7′,2″- [1,4]oxazinan]-15′-one- 13′,13′-dioxide 654.2135

See Example 138 (Steps 1- 2)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′-dimethyl-4″-(tetrahydro- 2H-pyran-4-ylmethyl)-3,4- dihydro-2H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraene-7′,2″- [1,4]oxazinan]-15′-one- 13′,13′-dioxide 752.3136

See Example 138 (Steps 1- 3)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-4″-(4-pyridinylmethyl)-3,4 dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one- 13′,13′-dioxide 745.3 137

See Example 138 (Steps 1- 3)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-4″-(3-pyridinylmethyl)-3,4- dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one- 13′,13′-dioxide 745.3 139

See Example 138 (Steps 1- 3)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-4″- (cyclohexylmethyl)-11′,12-dimethyl-3,4- dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one- 13′,13′-dioxide 750.3 140

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′(((9aS)-4- oxohexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide781.2

141

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aS)-4- oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro-2H,15′-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 781.2

142

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((3S,9aS)-3-methyl-4- oxohexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide795.3

143

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((3S,9aS)-3-methyl-4- oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 795.2

144

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((3R,9aS)-3-methyl-4- oxohexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide795.3

145

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((3S,9aS)-3- methylhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 781.4

146

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((3S,9aS)-3- methylhexahydropyrazino[2, 1-c][1,4]oxazin-8(1H)-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide781.2

147

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((3R,9aS)-3- methylhexahydropyrazino[2, 1-c][1,4]oxazin-8(1H)-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide781.2

148

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(3,4- dihydro-2(1H)-isoquinolinylmethyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H-15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide758.3

149

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((9aR)-4-oxooctahydro- 2H-pyrido[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide779.3 150

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((9aR)-4-oxooctahydro- 2H-pyrido[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide779.3 152

See example 151

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(2- methoxyethoxy)-11′,12′-dimethyl-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 809.2

153

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4-(2,2- dimethylpropyl)-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide781.3 155

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (cyclopropylmethoxy)-11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide805.3

156

2, 5, 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-10′,11′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 767

157

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-10′,11′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide767.2 \

158

2, 5, 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-methoxy-10′,11′-dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.2

159

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′- methoxy-10′,11′-dimethyl-7-′((4-(3-oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide767.2

160

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′- methoxy-10′,11′-dimethyl-7′-((4-methyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide725.2

161

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′- methoxy-10′,11′-dimethyl-7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide765.2

162

2, 5, 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-((3-(dimethylamino)-3-methyl- 1-azetidinyl)methyl)-7′-methoxy-10′,11′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide739.2

163

2, 5, 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-methoxy-10′,11′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide765.2

164

2, 5 (Step 1), 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-hydroxy-10′,11′-dimethyl-3,4- dihydro-2H-15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide753.2

165

2 (Step 1), 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′-hydroxy-10′,11′-dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 753.2

166

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′-ethoxy-10′,11′-dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 781.2

167

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′- methoxy-12′-(methoxymethyl)-11′- methyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.2

168

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-12′-(methoxymethyl)-11′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 797.2

169

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′- methoxy-12′-(methoxymethyl)-11′- methyl-7′-((9aR)- octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide795.2

170

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-methoxy-12′-(methoxymethyl)-11′- methyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.2

171

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2, 1-c][1,4]oxazin-8(1H)- ylmethyl)-12′-(methoxymethyl)-11′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 811.2

172

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-methoxy- 7′-((4-(methoxy-1-(methoxymethyl)ethyl)-1- piperazinyl)methyl)-12′- (methoxymethyl)-11′-methyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide843.2

173

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-methoxy-12′-(methoxymethyl)-11′- methyl-7′-((4-(1- methylethyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide783.4

174

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-7′-((4-tert-butyl-1-piperazinyl)methyl)-6- chloro-7′-methoxy-12′- (methoxymethyl)-11′-methyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.2

175

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′-ethoxy-12′-(methoxymethyl)-11′- methyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide811.2

178

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′- methoxy-12′-(2-methoxyethyl)-11′-methyl- 7′-((4-methyl-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 769.2

179

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 811.2

180

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′- methyl-7′-((4-methyl-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide769.2

181

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′- methoxy-12′-(2-methoxyethyl)-11′-methyl- 7′-((9aR)-octahydro-H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide809.0

182

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′- methyl-7′-((9aR)- octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide809.2

184

1, 5, 11

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-12′-(methoxymethyl)-11′- methyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.2

185

5, 11

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide768.2

186

5, 11

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide766.2 187

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′- methoxy-12′-(2-methoxyethyl)-11′-methyl- 7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide811.2

188

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′- methoxy-12′-(2-methoxyethyl)-11′-methyl- 7′-((4-(1-methylethyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.2 189

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-7′-((4-tert-butyl-1-piperazinyl)methyl)-6- chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide811.2 190

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-7′-((4-tert-butyl-1-piperazinyl)methyl)-6- chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide825.2

191

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-12′-(2-methoxyethyl)-11′-methyl- 7′-(((3R,5S)-3,4,5- trimethyl-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.2 192

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-12′-(2-methoxyethyl)-11′-methyl- 7′-((4-(3-methyl-3- oxetanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide825.2 195

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-7′-((4-(2-methoxyethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 769.2 196

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- methyl-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 725.3 197

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide765.3 198

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(2,5-dioxa-8-azaspiro[3.5]non- 8-ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 754.4 199

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-(((2R)-2-(methoxymethyl)-4- morpholinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 756.3

200

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(6,7- dihydroisoxazolo[4,3-c]pyridin-5(4H)-ylmethyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 749.3 201

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-ylmethyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 748.2 202

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((2,2- dioxido-2-thia-6-azaspiro[3.3]hept-6- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 772.3 203

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- oxa-6-azaspiro[3.3]hept-6-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide724.3 204

10

tert-butyl-6- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′-yl)methyl)-2,6-diazaspiro[3.3] heptane-2-carboxylate 823.3 205

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (1,4,6,7-tetrahydro-5H- [1,2,3]triazolo[4,5-c]pyridin-5-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide749.3 206

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((3,3- bis(hydroxymethyl)-1-azetidinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 742.3 207

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(6,7-dihydro[1,2,3]triazolo[1,5- a]pyrazin-5(4H)-ylmethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide749.5 208

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(6- oxa-1-azaspiro[3.3]hept-1-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide724.4

209

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(6,7-dihydro[1,3]thiazolo[5,4- c]pyridin-5(4H)ylmethyl)- 7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide765.5 210

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aR)-8- methyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(((9aS)-8-methyloctahydro- 2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′- 780.5

[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 211

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(5,8- dihydropyrido[3,4-d]pyrimidin-7(6H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 760.3 212

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-7′-((methoxy(methyl)amino) methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 686.5 214

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H-15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H-15′H- 808.3

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 215

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9ar)- 2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 815.3

11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 216

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aR)-8- methyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aS)-8-methyloctahydro-2H-pyrazino[1,2-a]pyrazin- 780.5

2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 217

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aR)-8- methyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aS)-8-methyloctahydro-2H-pyrazino[1,2-a]pyrazin- 780.5

2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 218

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- 808.3

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 219

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H-15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- 815.2 dihydro-2H-15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 220

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H-15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- 815.2

dihydro-2H-15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 221

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H-15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- 815.2

dihydro-2H-15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 222

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(7,8- dihydropyrido[4,3-d]pyrimidin-6(5H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 760.3 223

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(7,8- dihydropyrido[4,3-d]pyrimidin-6(5H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 760.2 224

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((2,2- dioxido-2-thia-6-azaspiro[3.3]hept-6- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 772.0 225

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- 808.3

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 226

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- 808.3

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 227

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-8- (methylsulfonyl)octahydro-2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(((9aS)-8-(methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] 844.3

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 228

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-8- (methylsulfonyl)octahydro-2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(((9aS)-8-(methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] 844.0

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 229

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- 808.2

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 230

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- 808.2

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 231

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- 815.1

dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 232

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-2,2-dioxidohexahydropyrazino[2, 1-c][1,4]thiazin-8(1H)-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- 815.1

dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 233

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aR)-8-(3- (phenylsulfonyl)propanoyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 963.7

11′,12′-dimethyl-7′- (((9aS)-8-(3- (phenylsulfonyl)propanoyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 234

Example 276

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aR)-8- acryloyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acryloyloctahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′-methoxy-11′,12′-dimethyl- 820.3

3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 235

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aR)-8-(1- methylethyl)octahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aS)-8-(1- methylethyl)octahydro-2H-pyrazino[1,2-a]pyrazin-2- 828.0

yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 236

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((9aR)- octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((9aR)- octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] 751.4

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 237

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((9aS)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((9aR)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 844.2

15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 238

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((9aS)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((9aR)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 844.2

15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 239

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(1- methylethyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 753.7 240

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aS)-8-(1- methylethyl)octahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8-(1-methylethyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 809.0

15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 241

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aS)-8-(1- methylethyl)octahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8-(1-methylethyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 809.0

15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 242

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] 751.4

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 243

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] 751.4

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 244

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aS)-8- (methylfulfonyl)octahydro-2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(((9aR)-8-(methylfulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] 844.3

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 245

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aS)-8- (methylfulfonyl)octahydro-2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(((9aR)-8-(methylfulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] 844.3

diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 246

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-7′-((4-(methoxyacetyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 783.2 247

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-ethyl-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide739.3 248

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- (2,2,2-trifluoroethyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide793.2 249

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((4-acetyl-1- piperazinyl)methyl)-6-chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide753.3 250

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.3 251

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- phenyl-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 787.2 252

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(2- pyridinyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 788.8 253

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3- pyridinyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 788.8 254

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(4- pyridinyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 788.8 255

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- (1,3-thiazol-2-yl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 794.8 256

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(2- pyrimidinyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 789.9 257

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(2- pyrazinyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 789.0 258

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((3-(4- morpholinyl)-1- azetidinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.8 259

10

4-(((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′-yl)methyl)-N,N-dimethyl-1- piperazinecarboxamide 782.9 260

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((3-(2-methoxyethyl)(methyl)amino)- 1-azetidinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 769.8 261

10

ethyl (4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′-yl)-methyl)-1-piperazinyl)acetate 797.0

262

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- (tetrahydro-2H-pyran-4-yl)-1-piperazinyl)methyl)- 3,4-dihydro-2H-15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide796.0 263

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(4- morpholinyl)-1- piperidinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 796.0 264

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3- oxa-9-azaspiro[5.5]undec-9-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide780.8 265

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- oxa-8-azaspiro[4.5]dec-8-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide766.2 266

10

methyl 4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′- yl)methyl)-1-piperazinecarboxylate 769.2 267

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- oxa-7-azaspiro[3.5]non-7-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide752.8 268

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3- methyl-3-oxetanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide781.8 269

10

methyl (4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′- yl)methyl)-1-piperazinyl)acetate 783.8 271

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((4R)-2-oxotetrahydro-2H- pyran-4-yl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((4S)-2-oxotetrahydro-2H- pyran-4-yl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- 810.0

[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 272

10

3-(4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′-yl)methyl)-1-piperazinyl)- 3-oxetanecarbonitrile 792.8 273

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- 801.9

dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 274

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H-15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8-fluorooctahydro-2H- 783.9

pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H-15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H-pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H-15′H-

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H-15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,

16,18,24]tetraen]-15′-one 13′,13′-dioxide 275

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((3R)-tetrahydro-3-furanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((3S)-tetrahydro-3-furanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 781.8

13′,13′-dioxide 277

See example 276

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9AR)-8- ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2- A]PYRAZIN-2- YL)METHYL)-6- CHLORO-7′-METHOXY-11′,12′-DIMETHYL-3,4- DIHYDRO-2H,15′H- SPIRO[NAPHTHALENE- 1,22′-[20]OXA[13]THIA[1,14] DIAZATETRACYCLO[14.7 .2.0~3,6~.0~19,24~]PENTACOSA[8,16,18,24] TETRAEN]-15′-ONE 13′,13′-DIOXIDE OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9AS)-8- 821.0

ACRYLOYLOCTAHYDRO- 2H-PYRAZINO[1,2- A]PYRAZIN-2- YL)METHYL)-6-CHLORO-7′-METHOXY- 11′,12′-DIMETHYL-3,4- DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE- 1,22′- [20]OXA[13]THIA[1,14] DIAZATETRACYCLO[14.7.2.0~3,6~.0~19,24~] PENTACOSA[8,16,18,24] TETRAEN]-15′-ONE13′,13′-DIOXIDE 278

Aqueous hydrolysis of lactone

(3R)-3-(4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′-yl)methyl)-1-piperazinyl)- 5-hydroxypentanoic acid AND (3S)-3-(4-(((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′- 828.0

yl)methyl)-1-piperazinyl)- 5-hydroxypentanoic acid 279

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((3-(1,1-dioxido-4-thiomorpholinyl)- 1-azetidinyl)methyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide815.1 280

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(1-acetyl-3-azetidinyl)-1- piperazinyl)methyl)-6- chloro-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide808.2 281

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4- cyclobutyl)-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H-15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide765.3 282

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(1- methyl-3-azetidinyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide780.2 283

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8-fluorooctahydro-2H- 783.9

pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H-pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,

16,18,24]tetraen]-15′-one 13′,13′-dioxide 284

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8-fluorooctahydro-2H- 783.9

pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H-pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-

[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide Or(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 285

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((3S)-tetrahydro-3-furanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((3R)-tetrahydro-3-furanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 781.3

13′,13′-dioxide 286

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((3S)-tetrahydro-3-furanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((3R)-tetrahydro-3-furanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 781.3

16,18,24]tetraen]-15′-one 13′,13′-dioxide 287

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-7′-((4-(2-methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)-11′,12′-dimethyl-3,4- dihydro-2H-15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide814.0 288

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- 801.9

dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 289

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- 801.9

dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 290

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((3- methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide795.9 291

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((7- methyl-6-oxo-5-oxa-2,7- diazaspiro[3.4]oct-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide767.8 292

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy11′,12′-dimethyl-3,4- 801.9

dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 293

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8-fluoroocthydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8-fluoroocthydro-2H- 783.9

pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (((8S,9aR)-8- fluoroocthydro-2H-pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8-fluoroocthydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,

16,18,24]tetraen]-15′-one 13′,13′-dioxide 294

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aS)-8-(3- (phenylsulfonyl)propanoyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8-(3- 962.2

(phenylsulfonyl)propanoyl) octahydro-2H- pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 295

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- (((9aS)-8-(3- (phenylsulfonyl)propanoyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8-(3-(phenylsulfonyl)propanoyl) octahydro-2H- pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 962.2 16,18,24]tetraen]-15′-one13′,13′-dioxide 296

10

(2-acetyl-4-(4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′- yl)methyl)-1-piperazinyl)phenyl)boronic acid 873.2 297

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-7′-((4-(2-methoxy-1,1- dimethylethyl)-1- piperazinyl)methyl)-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.2

298

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-8,8difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-8,8difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- 801.9

dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 299

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-8,8difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-8,8difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- 801.9

dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 300

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(2- hydroxyethyl)-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide755.2

301

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((4-butyl-1- piperazinyl)methyl)-6-chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide767.3

302

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-7′-((4-(3-methoxypropyl)- 1-piperazinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 783.2 303

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(2- ethoxyethyl)-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide783.3

304

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((4-(2-methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide813.2 305

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(5- pyrimidinyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 789.9 306

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(2,2- difluoroethyl)-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide775.8 307

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-((4-tert-butyl-1-piperazinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.8 308

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((4-(bis(2- methoxyethyl)amino)-1-piperidinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 842.1 309

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(1,3-dioxolan-2-ylmethyl)-1- piperazinyl)methyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.9

310

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(3- hydroxy-2-(hydroxymethyl)propyl)-1- piperazinyl)methyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide800.0 311

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-((4-(3- methyl-3-oxetanyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide796.0 312

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(bis(2-methoxyethyl)amino)-1- piperidinyl)methyl)-6- chloro-7′-ethoxy-11′,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide856.2 313

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3- oxetanylmethyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 781.8 314

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((1R,4R)-5-(1- methylethyl)-2,5- diazabicyclo[2.2.1]hept-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide765.8 315

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((1S,4S)-5-(1- methylethyl)-2,5- diazabicyclo[2.2.1]hept-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide765.8 316

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((5-methyl-1,2,4- oxadiazol-3-yl)methyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide807.9 317

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- ((3-methyl-1,2,4- oxadiazol-5-yl)methyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide807.9 318

10

3-(4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13-dioxido-15′-oxo- 3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-7′- yl)methyl)-1-piperazinyl)propanenitrile 764.8 319

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-(3-methyl-3- oxetanyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 782.0 320

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((6-(1-methylethyl)-2,6- diazaspiro[3.3]hept-2-yl)methyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide765.9 321

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4- (1,2,4-oxadiazol-3- ylmethyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide793.2 322

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-((4,5-dimethyl-1,3-oxazol-2- yl)methyl)-1- piperazinyl)methyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide820.3 323

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-(1-methyethyl)-3- oxo-1-piperazinyl)methyl)- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide767.3 324

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-(((3R,5S)-4-(2-methoxyethyl)-3,5- dimethyl-1- piperazinyl)methyl)-11′,12′-dimethyl-3,4- dihydro-2H,15′- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.3 325

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8-fluorooctahydro-2H- 783.9

pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H-pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide 326

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8-fluorooctahydro-2H- 783.9

pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H-pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8-fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,

16,18,24]tetraen]-15′-one 13′,13′-dioxide 327

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-(1-methylethyl)-1,4- diazepan-1-yl)methyl)-3,4- dihydro-2H-15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide767.3 328

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((3R,5S)-3,5-dimethyl-4-(1-methylethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 781.3 329

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((3R,5S)-3,5-dimethyl-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide739.2 330

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4- ethyl-3,3-dimethyl-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide767.2 331

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-(1-methylethyl)-1,4- diazepan-1-yl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-(1-methylethyl)-1,4- diazepan-1-yl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 767.2

16,18,24]tetraen]-15′-one 13′,13′-dioxide 332

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(2-(2-methocyethocy)ethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 813.2 333

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((4-(2-methoxy-1,1- dimethylethyl)-1- piperazinyl)methyl)-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.2 334

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-7′-((4-(2-methoxyethyl)- 3,3-dimethyl-1- piperazinyl)methyl)-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide797.2 335

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((4-ter-butyl-1-piperazinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.2 336

10

/ (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((3R,5S)-3,4,5-trimethyl- 1-piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 753.2 337

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((3S)-3-methyl-4-(1- methylethyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.2 338

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(2- pyrimidinylmethyl)-1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide803.2 339

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(1,1-dioxido-3-thietanyl)-1- piperazinyl)methyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide815.2 340

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(1,4- dioxepan-6-yl)-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide811.2 341

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((3R,5S)-4-ethyl-3,5-dimethyl-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.2 342

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4-(1,4- dioxepan-6-yl)-1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide811.2 343

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((3R,5R)-3,5-dimethyl-4-(1-methylethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihdydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 781.2 344

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((3-(bis(2- methocyethyl)amino)-1-azetidinyl)methyl)-6- chloro-7′-methoxy- 11′,12-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 813.2 346

5, 9

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-12′-(2-hydroxyethyl)-7′-methoxy- 11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 797.2 347

5, 9

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-7′-propoxy-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide795.3 349

5, Example 348 (Step 2), 9

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-7′-(2- methylpropoxy)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide809.2 350

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-(2-methylpropoxy)-7′-((9aR)- octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide807.4 351

5, Example 348 (Step 2), 9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-7′-propoxy-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide795.3 352

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-((4-(3-oxetanyl)-1- piperazinyl)methyl)-7′- propoxy-2,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 795.3

353

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-7′-propoxy-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide793.4

354

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-(2-methylpropoxy)-7′-((9aR)- octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide807.3

355

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-(2-methylpropoxy)-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 809.3

356

5, Example 348 (Step 2), 9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′-dimethyl-7′-(2- methylpropoxy)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide809.4

357

9, Example 367 (Step 11)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-12′-(2-hydroxyethyl)-7′-methoxy- 11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 797.4

360

See example 18 (Step 14)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′-methyl-7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrain-2- ylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-12′- yl)acetaldehyde 793.3 361

See example 367 (Steps 12, 13)

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′-methyl-12′-(2-(4- morpholinyl)ethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide866.4

365

See example 367 (Step 13)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′-methyl-12′-(2-(4-morpholinyl)ethyl)- 7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 864.3

368

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′-12′- dimethyl-7′-(((3R)-3-methyl-4-(2-propanyl)-1- piperazinyl)methyl)-7′- propoxy-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~ 3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 795.3 369

4, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-12′-(2-methoxyethyl)-11′-methyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide826.2 370

4, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′- methyl-7′-((9aR)- octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide824.3 371

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-7′-(((4-(2-methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide814.2 372

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2-ylmethyl)3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide766.3

Example 100001 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and (1S,3′R,6′R,7′S,8′F,11′,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a 250 mL round-bottomed flask was added 1,3-dithiane (4.79 g, 39.8mmol) and THF (100 mL). The mixture was cooled to −78° C. andn-butyllithium (1.6 M solution in hexane, 22.5 mL, 36.1 mmol) was addedover 8 min. The solution was stirred in the −78° C. bath for 30 min. Ina separate 100 mL flask was added(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide and THF (5 mL). To this was added lanthanum(III)chloride bis lithium chloride complex solution (0.6 M in THF, 60.1 mL,36.1 mmol) and this was stirred for 5 min at room temperature. Thesolution was then cooled to −78° C. and added via cannula to thedithiane solution. After 2.5 h at −78° C., the solution was treated withsat NH₄Cl and water. The pH of the solution was adjusted to pH=4 withaqueous 10% citric acid and aqueous NaHCO₃. The solution was extractedwith EtOAc and the combined extracts were filtered through Celite. Theextracts were washed with water and brine and then dried (Na₂SO₄) andconcentrated to afford a mixture of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a brown oil which was carried on directly to the nextstep. MS (ESI, +ve ion) m/z 717.5 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a resealable vial was added the mixture of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (6.81 g, 9.49 mmol) and THF (100 mL). The mixture wascooled to 0° C. and potassium bis(trimethylsilyl)amide (1 M in THF, 38.0mL, 38.0 mmol) was added over 10 min. The solution was stirred at 0° C.for 5 min and then iodomethane (2.36 mL, 38.0 mmol) was added over 3min. After 2.5 h at 0° C., the solution was poured into saturated NH₄Cland the pH was adjusted to 4 with 1 M citric acid. The solution wasextracted with EtOAc and the combined extracts were washed with brine,dried (Na₂SO₄) and concentrated onto silica. Purification by silica gelchromatography (0% to 35% EtOAc/heptane, with 0.3% AcOH, 330 g Redi-SepGold column) afforded(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (1.66 g, 2.27 mmol, 24% yield). MS (ESI, +ve ion) m/z731.5 (M+H)⁺ and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (4.69 g, 6.41 mmol, 68% yield). MS (ESI, +ve ion) m/z731.5 (M+H)⁺.

Step 3:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide

To a 250 mL round-bottomed flask equipped with a reflux condenser wasadded(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (1.63 g, 2.23 mmol), acetonitrile (40 mL) and water (10mL). The mixture was heated to 50° C. and calcium carbonate (1.12 g,11.1 mmol) and iodomethane (1.38 mL, 22.3 mmol) were added. After 23 hat 50° C., the solution was poured into saturated NH₄Cl and water andthen extracted with EtOAc. The combined extracts were washed with brineand then dried (Na₂SO₄) and concentrated onto silica. Purification bysilica gel chromatography (0 to 40% EtOAc/heptane (both with 0.3% AcOH),Silicycle HP 120 g column) afforded(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (1.34 g, 2.09 mmol, 94% yield) as a white solid. MS(ESI, +ve ion) m/z 641.3 (M+H)⁺.

Step 4:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a room temperature solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde13′,13′-dioxide (30 mg, 0.047 mmol) in MeOH (2 mL) and THF (0.5 mL), wasadded sodium borohydride (17 mg, 0.47 mmol). After 5 min at rt thesolution was poured into saturated NaCl and then extracted with EtOAc.The combined extracts were dried (Na₂SO₄) and concentrated. Purificationby silica gel chromatography (0% to 60% EtOAc (0.3% AcOH) in heptane (4g column)) afforded(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (10 mg, 0.016 mmol, 50% yield) as a white solid. ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.95-8.01 (m, 1H), 7.68 (d, J=8.61 Hz, 1H),7.16-7.20 (m, 1H), 7.10 (dd, J=1.86, 13.99 Hz, 2H), 6.85-6.95 (m, 2H),5.71-5.80 (m, 1H), 5.67 (d, J=0.98 Hz, 1H), 4.29-4.41 (m, 1H), 4.07 (d,J=4.89 Hz, 3H), 3.87-3.97 (m, 2H), 3.72 (br d, J=14.48 Hz, 1H), 3.26 (d,J=14.28 Hz, 1H), 3.10 (s, 3H), 2.96-3.04 (m, 1H), 2.72-2.80 (m, 2H),2.56-2.65 (m, 1H), 2.44 (s, 1H), 1.75-2.28 (m, 9H), 1.55-1.71 (m, 1H),1.50 (d, J=7.04 Hz, 3H), 1.50-1.41 (m, 1H), 1.06 (d, J=6.85 Hz, 3H). Oneexchangeable proton was not observed. MS (ESI, +ve ion) m/z 643.2(M+H)⁺.

Example 1000022-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylacetamide

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid (60 mg, 0.089 mmol) was taken up in THF (1.8 mL) and lithiumhydroxide (2.0 M in water, 0.18 mL, 0.36 mmol) was added. The mixturewas stirred at room temperature for 10 min before being concentrated invacuo to provide the lithium carboxylate of the starting material as anoff-white solid that was used in the amide coupling. HATU (51.0 mg,0.134 mmol) and dimethylamine (2.0 M in THF, 0.134 mL, 0.268 mmol) wereadded to a stirred suspension of the lithium carboxylate previouslyprepared in N,N-dimethylformamide (1.8 mL). The reaction mixture wasstirred at room temperature for 10 minutes. The reaction mixture wasdiluted with water and EtOAc and transferred to a separatory funnel. 1.0M HCl was added and the phases were mixed. The organic layer wasseparated and washed sequentially with 1.0 M LiCl and brine then driedover magnesium sulfate and concentrated under reduced pressure.Purification via silica gel flash chromatography using a gradient of 50%to 100% EtOAc+0.3% AcOH in heptane afforded2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylacetamide(38 mg, 0.054 mmol, 61% yield) as a white solid. ¹H NMR (300 MHz,CHLOROFORM-d) δ ppm 7.71 (d, J=8.48 Hz, 1H) 7.17 (dd, J=8.77, 2.19 Hz,1H) 7.07-7.11 (m, 1H) 7.01-7.04 (m, 1H) 6.95-7.00 (m, 1H) 6.88-6.93 (m,1H) 5.71-5.92 (m, 2H) 4.00-4.11 (m, 3H) 3.84 (br d, J=15.20 Hz, 1H) 3.70(br d, J=14.03 Hz, 1H) 3.30 (d, J=14.32 Hz, 1H) 3.17 (s, 3H) 3.08-3.15(m, 2H) 3.06 (s, 3H) 3.01 (s, 1H) 2.94 (s, 3H) 2.65-2.87 (m, 3H)2.39-2.65 (m, 3H) 2.02-2.21 (m, 4H) 1.51-1.97 (m, 11H) 1.30-1.47 (m, 5H)1.05 (d, J=6.14 Hz, 3H). MS (ESI, +ve) m/z 666.2 [M−OMe]⁺.

Example 100003(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A solution of 2-bromopyridine (105 μL, 1.1 mmol) in THF (4 mL) wascooled to −78° C. under nitrogen atmosphere. A solution ofn-butyllithium in hexanes (2.5 M, 422 μL, 1.1 mmol) was added dropwiseand the reaction mixture was stirred for 30 min. A solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (300 mg, 0.5 mmol) in THF (1 mL) was added dropwise andthe reaction mixture was allowed to warn to room temperature overnight.An aqueous saturated solution of NH₄Cl was added and the reactionmixture was extracted with EtOAc. The organic phase was separated,washed with brine and concentrated under reduced pressure. The yellowsolid was purified by column chromatography on silica gel, eluting witha gradient of 0 to 35% EtOAc (containing 0.3% HOAc)/hexane to obtain amixture of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a light-yellow solid (129 mg). The mixture was usedin the next step without additional purification. MS (ESI, +ve ion) m/z676.0 (M+H)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

The mixture of(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (129 mg, 0.19 mmol) was dissolved in THF (5 mL) and thesolution was cooled with a water bath. Sodium hydride (60% dispersion inmineral oil, 201 mg, 5 mmol) was added in one portion. After 15 min,iodomethane (624 μL, 10 mmol) was added. An additional portion of eachNaH and MeI were added after 2 h. An aqueous saturated solution of NH₄Clwas added and the reaction mixture was extracted with EtOAc. The solventwas removed under reduced pressure. The concentrate was purified bypreparative reversed-phase preparative HPLC using a Phenomenex Geminicolumn, 10 μm, C18, 110 Å, 100×50 mm, 0.1% TFA in CH₃CN/H₂O, gradient10% to 100% over 20 min to afford 21 mg of[(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide, the second eluting peak, as a white solid. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 1.15 (m, 3H) 1.24-1.34 (m, 2H) 1.48 (m, 3H)1.61-1.80 (m, 2H) 1.83-1.93 (m, 2H) 1.95-2.07 (m, 3H) 2.19-2.32 (m, 3H)2.62-2.82 (m, 5H) 3.06 (s, 3H) 3.11-3.21 (m, 2H) 3.70 (m, 1H) 3.96-4.01(m, 1H) 4.04-4.09 (m, 1H) 4.17 (m, 1H) 5.86-6.02 (m, 2H) 6.92-6.97 (m,1H) 6.99-7.03 (m, 1H) 7.09 (d, J=8.02 Hz, 2H) 7.18 (dd, J=8.41, 1.96 Hz,1H) 7.65-7.71 (m, 2H) 8.34-8.40 (m, 2H) 9.02 (d, J=5.09 Hz, 1H). MS(ESI, +ve ion) m/z 690.0 (M+H)⁺.

Example 100004(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of 2,2,6,6-tetramethylpiperidine (1.06 mL, 6.3 mmol) inTHF (28 mL) that was cooled to 0° C. was added a solution ofn-butyllithium (2.5 M in THF, 2.4 mL, 6.0 mmol) under nitrogenatmosphere. The reaction was stirred at 0° C. for 25 minutes then cooledto −78° C. A solution of pyridazine (110 μL, 1.5 mmol) in THF (5 mL) wasadded dropwise, followed by a solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (300 mg, 0.502 mmol) in THF (3 mL). The reaction mixturewas allowed to stir at −78° C. for 2 h and quenched by the addition ofaqueous saturated ammonium chloride solution. The reaction mixture wasextracted with EtOAc. The organic phase was separated, washed with brineand concentrated under reduced pressure to give the crude material. Thecrude material was purified by silica gel flash chromatography using agradient of 50% to 100% EtOAc+0.3% AcOH in heptane to provide 106 mg of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide, the second eluting peak. MS (ESI, +ve ion) m/z 677.0(M+H)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Sodium hydride (60% dispersion in mineral oil, 81 mg, 2.0 mmol) wasadded in one portion to a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (137 mg, 0.2 mmol) in tetrahydrofuran (6.7 mL). After 5min, iodomethane (251 μL, 4.1 mmol) was added and the reaction wasstirred for 2 hours. MeOH (3 mL) was added and the reaction mixture waspurified by preparative reversed-phase preparative HPLC using aPhenomenex Gemini column, 10 μm, C18, 110 Å, 100×50 mm, 0.1% TFA inCH₃CN/H₂O, gradient 10% to 100% over 20 min. The desired fractions werecombined and the solvent was removed under reduced pressure to obtain 92mg of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide as a tan solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.03 (d, J=6.06 Hz, 3H) 1.35 (d, J=6.65 Hz, 3H) 1.72-1.87 (m, 2H)1.89-2.23 (m, 9H) 2.73-2.84 (m, 3H) 2.94-3.06 (m, 2H) 3.11 (s, 3H) 3.26(d, J=14.48 Hz, 1H) 3.68 (d, J=7.04 Hz, 1H) 3.75 (d, J=14.48 Hz, 1H)4.04-4.14 (m, 2H) 4.32 (d, J=15.06 Hz, 1H) 5.43 (br. s., 9H) 5.91 (d,J=16.24 Hz, 1H) 6.85-6.92 (m, 2H) 7.03 (s, 1H) 7.09 (s, 1H) 7.16-7.21(m, 1H) 7.18 (d, J=8.61 Hz, 1H) 7.70 (d, J=8.41 Hz, 1H) 8.18 (br. s.,2H) 9.48 (br. s., 1H). MS (ESI, +ve ion) m/z 691.0 (M+H)⁺.

Example 1000052-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2-methoxyethyl)-N-methylacetamide

Step 1: 2-methyl-2-propanyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetateand 2-methyl-2-propanyl((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate

2-tert-Butoxy-2-oxoethylzinc chloride (0.5 M in diethyl ether, 48.6 mL,24.28 mmol) was added to a stirred solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (2.90 g, 4.86 mmol) in tetrahydrofuran (50 mL) under anitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched with saturatedaqueous NH₄Cl (150 mL) and extracted with EtOAc (100 mL). The organiclayer was separated, washed with 9:1 saturated aqueous NH₄Cl:30% aqueousNH₄OH (200 mL), washed with brine (100 mL), dried over MgSO₄, filtered,and concentrated in vacuo to provide a crude mixture of2-methyl-2-propanyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetateand 2-methyl-2-propanyl((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetatethat was azeotroped twice with toluene and used directly in the nextstep. MS (ESI, +ve) m/z 713.3 [M+H]⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Lithium borohydride (2.0 M solution in tetrahydrofuran, 10.41 mL, 20.82mmol) was added to a stirred solution of the crude mixture of2-methyl-2-propanyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetateand 2-methyl-2-propanyl((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetatein tetrahydrofuran (25 mL) under a nitrogen atmosphere. The reactionmixture was stirred at room temperature for 16 h. Additional lithiumborohydride (2.0 M solution in tetrahydrofuran, 5.21 mL, 10.4 mmol) wasadded, followed by dropwise addition of methanol (1.69 mL, 41.6 mmol).The reaction mixture was stirred at room temperature for 24 h.Additional methanol (1.687 mL, 41.6 mmol) was added, and the reactionmixture was stirred for another 2.5 h. The reaction mixture was slowlyquenched with saturated aqueous NH₄Cl (75 mL) and extracted twice withEtOAc (75 mL). The combined organic layers were separated, washed withbrine (60 mL), dried over MgSO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0 to 10% MeOHin DCM) provided a mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (2.58 g, 4.01 mmol, 96% yield) as a white solid. MS(ESI, +ve) m/z 643.2 [M+H]⁺.

Step 3:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Imidazole (1.274 g, 18.72 mmol) and tert-butyldimethylsilyl chloride(1.41 g, 9.36 mmol) were added to a stirred mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide and(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (3.01 g, 4.68 mmol) in dichloromethane (50 mL). Thereaction mixture was stirred at room temperature for 72 h. Additionaltert-butyldimethylsilyl chloride (1.41 g, 9.36 mmol) and imidazole(1.274 g, 18.72 mmol) were added, and the reaction mixture was stirredat room temperature for another 4 h. Additional reagents were addedmultiple times while stirring at room temperature until the reactionprogressed no further upon addition. The reaction mixture was quenchedwith saturated aqueous NH₄Cl (125 mL) and extracted with DCM (75 mL).The organic layer was separated, dried over MgSO₄, filtered, andconcentrated in vacuo. The resulting residue was resubjected to theoriginal reaction conditions and stirred at room temperature for 2 h.The reaction mixture was quenched with saturated aqueous NH₄Cl (125 mL)and extracted with DCM (75 mL). The organic layer was separated, driedover MgSO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0 to 50% EtOAc in heptane)provided(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (453 mg, 0.598 mmol, 13% yield), the second diastereomerto elute from the column, as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.99 (1H, s) 7.69 (1H, d, J=8.41 Hz) 7.18 (1H, dd,J=8.51, 2.25 Hz) 7.09 (1H, d, J=2.15 Hz) 6.92-6.96 (3H, m) 5.71-5.78(1H, m) 5.59 (1H, d, J=16.04 Hz) 4.55 (1H, br. s.) 3.96-4.19 (5H, m)3.67-3.82 (2H, m) 3.25 (1H, d, J=14.28 Hz) 3.02 (1H, dd, J=15.16, 10.27Hz) 2.68-2.86 (2H, m) 2.35-2.47 (1H, m) 2.26-2.36 (1H, m) 2.12-2.24 (3H,m) 1.77-2.08 (6H, m) 1.65-1.77 (1H, m) 1.51-1.62 (1H, m) 1.46 (3H, d,J=7.04 Hz) 1.36-1.45 (1H, m) 1.25-1.32 (1H, m) 1.07 (3H, d, J=6.06 Hz)0.91 (9H, s) 0.10 (6H, d, J=3.33 Hz). MS (ESI, +ve) m/z 757.2 [M+H]⁺.

Step 4:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Sodium hydride (60% dispersion in mineral oil, 119 mg, 2.97 mmol) wasadded to a stirred solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (225 mg, 0.297 mmol) and iodomethane (0.185 mL, 2.97mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred atroom temperature for 17 h. The reaction mixture was quenched withsaturated aqueous NH₄Cl (50 mL) and extracted with EtOAc (70 mL). Theorganic layer was separated, washed with brine (50 mL), dried overMgSO₄, filtered, and concentrated in vacuo to provide crude(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide that was used directly in the next step. MS (ESI, +ve)m/z 793.3 [M+Na]⁺.

Step 5:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.356mL, 0.356 mmol) was added to a stirred solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (229 mg, 0.297 mmol) in tetrahydrofuran (1.5 mL). Thereaction mixture was stirred at room temperature for 3.5 h. Additionaltetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.356mL, 0.356 mmol) was added, and the reaction mixture was stirred foranother 3 h. The reaction mixture was concentrated. Chromatographicpurification of the residue (silica gel, 0 to 100% (EtOAc with 0.3%AcOH) in heptane) provided(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (178 mg, 0.271 mmol, 91% yield) as a white solid. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 8.10 (1H, s) 7.68 (1H, d, J=8.61 Hz) 7.18(1H, dd, J=8.51, 2.25 Hz) 7.09 (1H, d, J=2.15 Hz) 6.88-6.96 (3H, m)5.75-5.83 (1H, m) 5.64 (1H, d, J=16.24 Hz) 4.29-4.37 (1H, m) 4.02-4.15(2H, m) 3.91-3.99 (1H, m) 3.80-3.88 (2H, m) 3.72 (1H, d, J=14.28 Hz)3.25 (1H, d, J=14.28 Hz) 3.11 (3H, s) 3.02 (1H, dd, J=14.96, 10.66 Hz)2.69-2.85 (2H, m) 2.59 (1H, q, J=9.06 Hz) 2.34-2.47 (2H, m) 2.12-2.24(2H, m) 1.76-2.06 (8H, m) 1.58-1.67 (1H, m) 1.50 (3H, d, J=7.04 Hz) 1.38(1H, t, J=12.91 Hz) 1.06 (3H, d, J=6.85 Hz). MS (ESI, +ve) m/z 657.2[M+H]⁺.

Step 6:((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehyde

Dess-Martin periodinane (67.4 mg, 0.159 mmol) was added to a stirredmixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (87 mg, 0.13 mmol) and sodium bicarbonate (111 mg, 1.32mmol) in dichloromethane (1 mL). The reaction mixture was stirred atroom temperature for 45 min. The reaction mixture was quenched withsaturated aqueous NaHCO₃(25 mL) and extracted with EtOAc (30 mL). Theorganic layer was separated, washed with 1 M aqueous Na₂S₂O₃ (20 mL),washed with brine (20 mL), dried over MgSO₄, filtered, and concentratedin vacuo to provide crude((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehydethat was used directly in the next step.

Step 7:((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid

A solution of potassium phosphate monobasic (361 mg, 2.66 mmol) andsodium chlorite (240 mg, 2.66 mmol) in water (2 mL) was added to astirred mixture of((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehyde(174 mg, 0.266 mmol) and 2-methyl-2-butene (1.407 mL, 13.28 mmol) intert-butanol (2 mL). The reaction mixture was stirred at roomtemperature for 45 min. The reaction mixture was diluted with EtOAc (50mL), washed with 1 M aqueous HCl (40 mL), washed with 1 M Na₂S₂O₃ (40mL), washed with brine (40 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. Chromatographic purification of the residue(silica gel, 0 to 100% (EtOAc with 0.3% AcOH) in heptane) provided((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid (142 mg, 0.212 mmol, 80% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.11 (1H, s) 7.68 (1H, d, J=8.41 Hz) 7.17 (1H, d,J=8.41 Hz) 7.08 (1H, s) 6.87-6.95 (3H, m) 5.80-5.90 (1H, m) 5.72 (1H, d,J=15.85 Hz) 4.36 (1H, q, J=7.17 Hz) 4.07 (2H, s) 3.99 (1H, d, J=15.65Hz) 3.71 (1H, d, J=14.48 Hz) 3.16-3.27 (5H, m) 3.01 (1H, dd, J=15.55,10.86 Hz) 2.71-2.84 (3H, m) 2.66 (1H, q, J=9.00 Hz) 2.42 (1H, quin,J=9.15 Hz) 2.12-2.26 (2H, m) 2.01-2.09 (1H, m) 1.83-2.01 (5H, m) 1.79(1H, d, J=7.24 Hz) 1.57-1.69 (1H, m) 1.51 (3H, d, J=7.04 Hz) 1.35 (1H,t, J=13.11 Hz) 1.06 (3H, d, J=6.65 Hz). MS (ESI, +ve) m/z 671.2 [M+H]⁺.

Step 8:2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2-methoxyethyl)-N-methylacetamide

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid (28 mg, 0.042 mmol) was taken up in THF (0.5 mL) and lithiumhydroxide (2.0 M in water, 0.083 mL, 0.17 mmol) was added. The mixturewas stirred at room temperature for 10 min before being concentrated invacuo to provide the lithium carboxylate of the starting material as anoff-white solid that was used in the amide coupling. HATU (31.7 mg,0.083 mmol) and N-(2-methoxyethyl)methylamine (0.022 mL, 0.21 mmol) wereadded to a stirred suspension of the lithium carboxylate previouslyprepared in N,N-dimethylformamide (0.50 mL). The reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was quenchedwith saturated aqueous NH₄Cl (20 mL) and extracted with EtOAc (30 mL).The organic layer was separated, washed with brine (15 mL), dried overMgSO₄, filtered, and concentrated in vacuo. Chromatographic purificationof the residue (silica gel, 0 to 100% (EtOAc with 0.3% AcOH) in heptane)followed by chromatographic purification (silica gel, 0 to 100% EtOAc inheptane) provided2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2-methoxyethyl)-N-methylacetamide(23 mg, 0.031 mmol, 74% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.27 (0.4H, s) 8.10 (0.6H, s) 7.69 (1H, d, J=8.61Hz) 7.17 (1H, dd, J=8.41, 2.15 Hz) 7.08 (1H, d, J=1.96 Hz) 6.90-7.06(3H, m) 5.84-5.90 (1H, m) 5.72-5.83 (1H, m) 4.28 (0.6H, q, J=7.04 Hz)4.19 (0.4H, q, J=7.04 Hz) 4.05 (1.2H, s) 4.04 (0.8H, s) 3.95 (0.4H, d,J=10.17 Hz) 3.91 (0.6H, d, J=10.17 Hz) 3.52-3.77 (4H, m) 3.22-3.34 (7H,m) 2.97-3.19 (6H, m) 2.57-2.82 (4H, m) 2.38-2.54 (1H, m) 1.99-2.23 (4H,m) 1.72-1.99 (5H, m) 1.57-1.68 (1H, m) 1.46-1.51 (3H, m) 1.27-1.37 (1H,m) 1.04-1.11 (3H, m). MS (ESI, +ve) m/z 742.2 [M+H]⁺.

Example 100006(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid (28 mg, 0.042 mmol) was taken up in THF (0.5 mL) and lithiumhydroxide (2.0 M in water, 0.083 mL, 0.17 mmol) was added. The mixturewas stirred at room temperature for 10 min before being concentrated invacuo to provide the lithium carboxylate of the starting material as anoff-white solid that was used in the amide coupling. HATU (31.7 mg,0.083 mmol) and azetidine (0.014 mL, 0.209 mmol) were added to a stirredsuspension of the lithium carboxylate previously prepared inN,N-dimethylformamide (0.25 mL). The reaction mixture was stirred atroom temperature for 1 h. The reaction mixture was quenched withsaturated aqueous NH₄Cl (10 mL) and extracted with EtOAc (15 mL). Theorganic layer was separated, washed with brine (10 mL), dried overMgSO₄, filtered, and concentrated in vacuo. Chromatographic purificationof the residue (silica gel, 0 to 100% (EtOAc with 0.3% AcOH) in heptane)followed by chromatographic purification (silica gel, 0 to 100% EtOAc inheptane) provided(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (22 mg, 0.031 mmol, 74% yield) as a white solid. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 8.21 (1H, br s) 7.68 (1H, d, J=8.61 Hz)7.13-7.20 (1H, m) 7.06-7.09 (1H, m) 6.88-6.97 (3H, m) 5.70-5.86 (2H, m)4.23-4.39 (3H, m) 3.98-4.11 (5H, m) 3.70 (1H, d, J=14.28 Hz) 3.22-3.32(2H, m) 3.08-3.18 (4H, m) 2.81-2.88 (1H, m) 2.67-2.79 (2H, m) 2.33-2.46(2H, m) 2.19-2.31 (2H, m) 1.72-2.19 (9H, m) 1.56-1.69 (1H, m) 1.49 (3H,d, J=6.85 Hz) 1.25-1.36 (1H, m) 1.06 (3H, d, J=6.65 Hz). MS (ESI, +ve)m/z 710.2 [M+H]⁺.

Example 100007 and Example 100016(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′,11′,12′-trimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 100007) and(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Example 100016)

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Lanthanum(III) chloride bis(lithium chloride) complex (0.5 M solution inTHF, 0.616 mL, 0.308 mmol) was added to a stirred solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (184 mg, 0.308 mmol) in tetrahydrofuran (3 mL) at 0° C.The mixture was stirred at 0° C. for 45 min before methylmagnesiumbromide (3.0 M solution in diethyl ether, 0.462 mL, 1.39 mmol) was addeddropwise via syringe. The reaction mixture was allowed to warm to roomtemperature and stirred for 18 h. The reaction mixture was quenched withsaturated aqueous NH₄Cl (30 mL) and extracted with EtOAc (45 mL). Theorganic layer was separated, washed with brine (30 mL), dried overMgSO₄, filtered, and concentrated in vacuo. Chromatographic purificationof the residue (silica gel, 0 to 75% (EtOAc with 0.3% AcOH) in heptane)provided(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (92 mg, 0.150 mmol, 49% yield), the second diastereomerto elute from the column, as a white solid. ¹H NMR (400 MHz,DICHLOROMETHANE-d₂) δ 7.71 (d, J=8.6 Hz, 1H), 7.18 (dd, J=2.2, 8.5 Hz,1H), 7.10 (d, J=2.2 Hz, 1H), 7.00-6.89 (m, 3H), 5.90-5.76 (m, 2H),4.35-4.24 (m, 1H), 4.11-4.04 (m, 2H), 3.84 (br d, J=14.9 Hz, 1H), 3.73(d, J=14.3 Hz, 1H), 3.28 (d, J=14.3 Hz, 1H), 3.05 (dd, J=10.4, 15.3 Hz,1H), 2.86-2.70 (m, 2H), 2.46-2.33 (m, 1H), 2.27 (q, J=9.3 Hz, 1H),2.18-2.10 (m, 1H), 2.07 (br d, J=2.5 Hz, 1H), 2.05-2.01 (m, 2H),2.02-1.91 (m, 3H), 1.89-1.78 (m, 3H), 1.69-1.60 (m, 1H), 1.52 (s, 3H),1.47 (d, J=7.2 Hz, 3H), 1.44-1.36 (m, 1H), 1.04 (d, J=6.8 Hz, 3H). MS(ESI, +ve) m/z 613.3 [M+H]⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′,11′,12′-trimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (33 mg, 0.054 mmol), 4-(2-bromoethyl)morpholinehydrobromide (296 mg, 1.08 mmol), and sodium hydride (60% dispersion inmineral oil, 86 mg, 2.2 mmol) were mixed in N,N-dimethylformamide (1.5mL). The reaction mixture was stirred at room temperature for 20 h. Thereaction mixture was quenched with saturated aqueous NH₄Cl (20 mL) andextracted two times with EtOAc (30 mL). The combined organic layers werewashed with brine (15 mL), dried over MgSO₄, filtered, and concentratedin vacuo. Chromatographic purification of the residue (silica gel, 50%to 100% EtOAc in DCM until the starting material eluted and then 0 to10% (2 M NH₃ in MeOH) in DCM) provided(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′,11′,12′-trimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (25 mg, 0.034 mmol, 64% yield) as an off-white solid. ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.68 (1H, d, J=8.41 Hz) 7.17 (1H, dd,J=8.41, 2.15 Hz) 7.08 (1H, d, J=2.15 Hz) 6.89-6.96 (3H, m) 5.82 (1H,ddd, J=15.85, 9.59, 2.74 Hz) 5.65 (1H, d, J=15.85 Hz) 4.29 (1H, q,J=7.11 Hz) 4.00-4.11 (2H, m) 3.83 (1H, d, J=14.67 Hz) 3.68-3.77 (5H, m)3.33-3.46 (2H, m) 3.26 (1H, d, J=14.28 Hz) 3.00 (1H, dd, J=15.16, 10.66Hz) 2.69-2.84 (2H, m) 2.52-2.61 (6H, m) 2.40 (1H, quin, J=8.95 Hz) 2.28(1H, q, J=9.13 Hz) 1.74-2.21 (9H, m) 1.52-1.64 (1H, m) 1.48 (3H, d,J=7.04 Hz) 1.33-1.43 (4H, m) 1.04 (3H, d, J=6.85 Hz). MS (ESI, +ve) m/z726.3 [M+H]⁺.

Example 1000082-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N-(2-methyl-2-propanyl)acetamide

A drop of DMF was added to a stirred solution of oxalyl chloride (10 μL,0.11 mmol) and((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid (37 mg, 0.055 mmol) in dichloromethane (1 mL). The reaction mixturewas stirred at room temperature for 20 min before being concentrated invacuo. The resulting yellow residue was taken up in dichloromethane (1mL) and N-tert-butylmethylamine (0.066 mL, 0.55 mmol) was added. Thereaction mixture was stirred at room temperature for 40 min. Thereaction mixture was quenched with saturated aqueous NH₄Cl (20 mL) andextracted with EtOAc (30 mL). The organic layer was separated, washedwith brine (20 mL), dried over MgSO₄, filtered, and concentrated invacuo. Chromatographic purification of the residue (silica gel, 0 to 50%(EtOAc with 0.3% AcOH) in heptane) provided2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N-(2-methyl-2-propanyl)acetamide(18 mg, 0.024 mmol, 44% yield) as an off-white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.01 (1H, s) 7.68 (1H, d, J=8.41 Hz) 7.17 (1H, dd,J=8.51, 2.25 Hz) 7.08 (1H, d, J=1.96 Hz) 6.88-6.96 (3H, m) 5.68-5.81(2H, m) 4.33 (1H, q, J=7.43 Hz) 4.07 (2H, s) 3.85 (1H, d, J=15.06 Hz)3.71 (1H, d, J=14.28 Hz) 3.22-3.36 (2H, m) 3.11 (3H, s) 3.01-3.09 (5H,m) 2.68-2.84 (2H, m) 2.59 (1H, d, J=15.85 Hz) 2.33-2.44 (1H, m)2.06-2.23 (2H, m) 1.74-2.06 (7H, m) 1.55-1.66 (1H, m) 1.24-1.52 (13H, m)1.06 (3H, d, J=6.65 Hz). MS (ESI, +ve) m/z 762.3 [M+Na]⁺.

Example 1000092-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methylacetamide

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)aceticacid (50 mg, 0.074 mmol) was taken up in THF (2 mL) and lithiumhydroxide (2.0 M in water, 0.149 mL, 0.358 mmol) was added. The mixturewas stirred at room temperature for 10 min before being concentrated invacuo to provide the lithium carboxylate of the starting material as anoff-white solid that was used in the amide coupling. HATU (42.0 mg,0.112 mmol) and methylamine (2.0 M in THF, 0.112 mL, 0.223 mmol) wereadded to a stirred suspension of the lithium carboxylate previouslyprepared in N,N-dimethylformamide (2 mL). The reaction mixture wasstirred at room temperature for 30 minutes. The reaction mixture wasdiluted with water and EtOAc and transferred to a separatory funnel. 1.0M HCl was added and the phases were mixed. The organic layer wasseparated and washed sequentially with 1.0 M LiCl and brine then driedover magnesium sulfate and concentrated under reduced pressure.Purification via silica gel flash chromatography using a gradient of 50%to 100% EtOAc with 0.3% AcOH in heptane afforded2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methylacetamide(44 mg, 0.064 mmol, 86% yield) as a white solid. ¹H NMR (300 MHz,DICHLOROMETHANE-d₂) δ 7.69-7.79 (m, 1H) 7.19 (br dd, J=8.84, 1.10 Hz,1H) 7.12 (s, 1H) 6.88-7.03 (m, 3H) 6.74-6.86 (m, 1H) 5.75-5.89 (m, 1H)5.62-5.73 (m, 1H) 4.21-4.36 (m, 1H) 4.09 (s, 2H) 3.91-4.04 (m, 1H) 3.72(br d, J=15.05 Hz, 1H) 3.29 (br d, J=14.03 Hz, 1H) 3.16 (s, 3H)2.92-3.09 (m, 2H) 2.73-2.90 (m, 6H) 2.51-2.66 (m, 2H) 2.37-2.49 (m, 1H)1.67-2.25 (m, 11H) 1.48 (br d, J=7.02 Hz, 3H) 1.22-1.43 (m, 6H) 1.06 (brd, J=6.58 Hz, 3H). MS (ESI, +ve) m/z 652.0 [M−OMe]⁺.

Example 100010(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1: methyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate

A flame dried round bottom flask was charged with tetrahydrofuran (6.28mL) and lithium diisopropylamide (2.0 M solution inheptane/tetrahydrofuran/ethylbenzene, 7.54 mL, 15.1 mmol). The solutionwas cooled to −78° C. then a solution of methyl acetate (1.197 mL, 15.07mmol) in tetrahydrofuran (6.28 mL) was added dropwise and the reactionwas stirred at −78° C. for 45 minutes. The flask was equipped with anaddition funnel which was then charged with a solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (1.5 g, 2.5 mmol) in tetrahydrofuran (12.56 mL). Thereaction was stirred at −78° C. for 30 minutes. The reaction wasquenched with water and warmed to room temperature. The reaction wasdiluted with water and EtOAc and transferred to a separatory funnel. 1 MHCl was added. The phases were mixed and the organic layer wasseparated, washed with brine, dried over magnesium sulfate andconcentrated under reduced pressure. The crude residue was purified viasilica gel flash chromatography using a gradient of 20% to 70% EtOAcwith 0.3% AcOH in heptane to afford methyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate(0.666 g, 0.992 mmol, 40% yield), the second eluting diastereomer, as awhite solid. ¹H NMR (300 MHz, DICHLOROMETHANE-d₂) δ 8.06-8.25 (m, 1H)7.74 (d, J=8.62 Hz, 1H) 7.20 (br d, J=8.77 Hz, 1H) 7.13 (s, 1H) 6.96 (s,2H) 6.92 (s, 1H) 5.64-5.81 (m, 2H) 4.06-4.25 (m, 3H) 3.80 (s, 3H) 3.75(br d, J=14.03 Hz, 1H) 3.70 (s, 1H) 3.31 (d, J=14.18 Hz, 1H) 3.00-3.11(m, 1H) 2.91-3.00 (m, 1H) 2.69-2.87 (m, 3H) 2.32-2.56 (m, 2H) 1.79-2.21(m, 9H) 1.59-1.71 (m, 2H) 1.46 (d, J=7.16 Hz, 4H) 1.34-1.39 (m, 4H) 1.06(d, J=6.58 Hz, 3H). MS (ESI, +ve) m/z 671.2 [M+H]⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of methyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate(0.343 g, 0.511 mmol) in THF (10.22 mL) was added lithium hydroxide (2.0M in water, 0.639 mL, 1.28 mmol). The reaction was stirred at roomtemperature overnight. The reaction was concentrated under reducedpressure and used without further purification. To a suspension of thelithium carboxylate previously generated in DMF (2.5 mL) was added HATU(0.069 g, 0.18 mmol) followed by pyrrolidine (0.050 mL, 0.60 mmol). Thereaction was stirred at room temperature for 30 minutes. The reactionwas diluted with water and EtOAc and transferred to a separatory funnel.1.0 M HCl was added and the phases were mixed. The organic layer wasseparated then washed sequentially with 1.0 M LiCl and brine then driedover magnesium sulfate and concentrated under reduced pressure.Purification via silica gel flash chromatography using a gradient of 75%to 100% EtOAc with 0.3% AcOH in heptane afforded(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.0608 g, 0.086 mmol, 71% yield) as a white solid. MS(ESI, +ve) m/z 710.3 [M+H]⁺.

Step 3:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

A solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.0608 g, 0.086 mmol) in THF (0.856 mL) was cooled to0° C. before adding sodium hydride (0.017 g, 0.428 mmol). The reactionwas stirred for 30 minutes then iodomethane (0.053 mL, 0.856 mmol) wasadded and the reaction was warmed to room temperature and stirred for 1hour. A larger portion of iodomethane (0.150 mL) was added and thereaction was allowed to stir at room temperature overnight. Anadditional portion of MeI (0.15 mL) was added and the reaction wascontinued at room temperature for 6 h. The reaction was quenched withwater and diluted with water and EtOAc. The reaction was transferred toa separatory funnel and 1 M HCl was added. The phases were mixed and theorganic layer was separated, washed with brine and dried over magnesiumsulfate. The crude material was purified via silica gel flashchromatography using 100% EtOAc with 0.6% AcOH. The reaction wasrepeated a second time on the same scale and the material from bothreactions was combined and further purified by preparative supercriticalfluid chromatography SFC using the following conditions: Diol Column(21.2×250 mm, 5 m); 20% MeOH with 20 mM NH₃ in CO₂ to afford(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.018 g, 0.025 mmol, 15% yield) as a white solid. ¹HNMR (300 MHz, DICHLOROMETHANE-d₂) δ 7.75 (br d, J=8.18 Hz, 1H) 7.20 (brd, J=8.48 Hz, 1H) 7.12 (br s, 2H) 7.00-7.06 (m, 1H) 6.90-6.98 (m, 1H)5.75-5.99 (m, 2H) 4.13-4.24 (m, 1H) 4.10 (s, 2H) 3.86-3.96 (m, 1H) 3.74(br d, J=14.32 Hz, 1H) 3.57-3.68 (m, 2H) 3.41-3.54 (m, 2H) 3.34 (br d,J=14.62 Hz, 1H) 3.07-3.25 (m, 4H) 3.03 (br d, J=15.93 Hz, 1H) 2.69-2.92(m, 2H) 2.46-2.67 (m, 2H) 2.04-2.26 (m, 4H) 1.74-2.03 (m, 9H) 1.49-1.73(m, 9H) 1.46 (br d, J=6.72 Hz, 3H) 1.29-1.41 (m, 2H) 1.03-1.14 (m, 3H).MS (ESI, +ve) m/z 692.2 [M−OMe]⁺.

Example 100011(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a cooled (−78° C.) solution of 4-(tert-butyldimethylsilyl)-1-butyne(2.50 mL, 12.1 mmol) in tetrahydrofuran (30 mL) was added 2.5 Mbutyllithium in toluene (4.0 mL, 10 mmol) dropwise via syringe over aperiod of 15 min. After 1 h, a solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (1.008 g, 1.688 mmol) in THF (10 mL) was added dropwiseand stirred for 1 h. The reaction was quenched with pH 7 buffer (10 mL)and warmed to room temperature. The aqueous layer was extracted withEtOAc (3×). The combined organic layers were washed with brine and driedover Na₂SO₄. The solution was filtered, evaporated onto silica gel andpurified by flash chromatography (Isco, 40 g) eluting with 0.3% AcOH inEtOAc: 0.3% AcOH in heptane (0:1 to 1:3) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (468 mg, 36% yield) as a white solid. MS (ESI, +ve ion)m/z 763.4 (M+1)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a cooled (0° C.) solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.510 g, 0.653 mmol) in tetrahydrofuran (10 mL) wasadded 60% sodium hydride in mineral oil (0.211 g, 5.28 mmol) inportions. After 15 min iodomethane (0.160 mL, 2.58 mmol) was added andthe reaction was allowed to warm to room temperature overnight. Thereaction mixture was quenched with pH 7 buffer and partitioned betweenEtOAc and water. The aqueous layer was extracted with EtOAc (3×) thenthe combined organic layers were washed with brine, evaporated ontosilica gel and purified by flash chromatography (Isco, 25 g) elutingwith 0.3% AcOH in EtOAc: 0.3% AcOH in heptane (0:1 to 1:3) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (368 mg, 71% yield) as a white solid.MS (ESI, +ve ion) m/z 795.4 (M+1)⁺.

Step 3:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a room temperature solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.365 g, 0.459 mmol) in tetrahydrofuran (5 mL) wasadded 1 M tetrabutylammonium fluoride in tetrahydrofuran (1.5 mL, 1.5mmol) via syringe. The reaction was evaporated onto silica gel andpurified by flash chromatography (Isco (12 gram HP)) eluting with 0.3%AcOH in EtOAc: 0.3% AcOH in heptane (0:1 to 1:1) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (279 mg, 89% yield) as a white solid. MS (ESI, +ve ion)m/z 681.3 (M+1)⁺.

Step 4:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a cooled (0° C.) solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.023 g, 0.034 mmol) in dichloromethane (1 mL) wasadded triethylamine (0.020 mL, 0.14 mmol) followed by methanesulfonylchloride (0.015 mL, 0.19 mmol) and the reaction was stirred for 20 min.To the reaction was added a slurry of(S)-octahydropyrazino[2,1-c]morpholine dihydrochloride (0.067 g, 0.31mmol) and triethylamine in dichloromethane (1 mL) and the reaction wasstirred at room temperature for 85 h and at 45° C. for 4 h. The reactionwas cooled to room temperature, diluted with DCM, evaporated onto silicagel and purified by flash chromatography (Isco, 4 g) eluting with 25%EtOH/EtOAc: heptane (0:1 to 1:0) to give (12.6 mg, 46% yield)light-yellow solid. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.72 (d, J=8.41 Hz, 1H),7.20 (s, 1H), 7.17 (dd, J=8.51, 2.05 Hz, 1H), 7.09 (d, J=2.15 Hz, 1H),6.85-6.98 (m, 2H), 6.20-6.39 (m, 1H), 5.52 (d, J=15.84 Hz, 1H), 4.32 (d,J=15.65 Hz, 1H), 4.26 (d, J=6.46 Hz, 1H), 4.14 (d, J=12.13 Hz, 1H),4.00-4.11 (m, 2H), 3.75 (dd, J=11.15, 2.93 Hz, 1H), 3.69 (d, J=14.08 Hz,1H), 3.51-3.64 (m, 2H), 3.27 (d, J=14.28 Hz, 1H), 3.07-3.19 (m, 4H),3.01 (dd, J=15.26, 10.37 Hz, 1H), 2.87 (d, J=7.43 Hz, 1H), 2.74-2.83 (m,3H), 2.50-2.72 (m, 8H), 2.37-2.49 (m, 1H), 2.08-2.27 (m, 7H), 1.77-1.99(m, 5H), 1.57-1.75 (m, 2H), 1.34-1.51 (m, 4H), 1.03 (d, J=6.85 Hz, 3H).MS (ESI, +ve ion) m/z 805.3 (M+1)⁺.

Example 100012(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′S,8′E,11′,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]dizatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and(1S,3′R,6′R,7′S,8′E,11′,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]dizatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a cooled (−78° C.) solution of4-(tert-butyldimethylsilyloxy)-1-butyne (0.600 mL, 2.91 mmol) intetrahydrofuran (9 mL) was added 2.5 M butyllithium solution in toluene(1.00 mL, 2.50 mmol) dropwise over a period of 10 min. After 1 h, asolution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (0.249 g, 0.417 mmol) in THF (2 mL) was added dropwisevia syringe. After 1 h the reaction mixture was quenched with pH 7buffer, partitioned between EtOAc and brine and the aqueous layer wasextracted with EtOAc (3×). The combined organic layers were evaporatedonto silica gel and purified by flash chromatography (Isco, 12 g)eluting with 0.3% AcOH in EtOAc: 0.3% AcOH in heptane (0:1 to 1:3) togive(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (254 mg, 78% yield) as a white solid. MS (ESI, +ve ion)m/z 784.5 (M+1)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a cooled (0° C.) solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.254 g, 0.325 mmol) in tetrahydrofuran (5 mL) wasadded 60% NaH in mineral oil (0.105 g, 2.63 mmol) portion wise. After 10min iodomethane (0.080 mL, 1.3 mmol) was added via syringe and thereaction was allowed to warm to room temperature overnight. The reactionmixture was quenched with pH 7 buffer and partitioned between EtOAc andwater. The aqueous layer was extracted with EtOAc (3×) then the combinedorganic layers were washed with brine, evaporated onto silica gel andpurified by flash chromatography (Isco, 25 g) eluting with 0.3% AcOH inEtOAc: 0.3% AcOH in heptane (0:1 to 1:3) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (173 mg, 67% yield) as a white solid. MS (ESI, +ve ion)m/z 796.3 (M+1)⁺.

Step 3:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a room temperature solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.173 g, 0.217 mmol) in tetrahydrofuran (3 mL) wasadded 1 M tetrabutylammonium fluoride solution in THF (0.700 mL, 0.700mmol). The reaction was partitioned between EtOAc and brine and theorganic layer was evaporated onto silica gel and purified by flashchromatography (Isco (12 gram)) eluting with 25% EtOH/EtOAc:heptane (0:1to 1:0) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (91 mg, 61% yield) as a white solid.

Step 4:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a cooled (0° C.) solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (0.057 g, 0.084 mmol) in dichloromethane (1.5 mL) wasadded triethylamine (0.060 mL, 0.43 mmol) followed by methanesulfonylchloride (0.035 mL, 0.45 mmol) resulting in a yellow mixture. After 15min morpholine (0.075 mL, 0.86 mmol) was added the reaction was stirredfor 1 h. To the reaction was added morpholine (0.035 mL) and thereaction was stirred at room temperature overnight. The reaction mixturewas partitioned between CH₂Cl₂ and brine and the aqueous layer wasextracted with CH₂Cl₂ and brine (2×). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure togive 110 mg of a yellow tar. The material was purified following a2-step SFC method: (Step 1: Cyano column, 20% isopropanol/20 mM NH₃ 80g/min Step 2: MSA column, 40% MeOH/20 mM NH₃) to give the first elutingisomer,(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (6 mg, 10% yield) as a white crystalline solid. ¹H NMR(400 MHz, CD₂Cl₂) δ 7.72 (d, J=8.41 Hz, 1H), 7.19 (s, 1H), 7.17 (dd,J=8.51, 2.25 Hz, 1H), 7.09 (d, J=2.15 Hz, 1H), 6.80-6.95 (m, 2H),6.23-6.39 (m, 1H), 5.52 (d, J=15.26 Hz, 1H), 4.39 (d, J=14.87 Hz, 1H),4.26-4.34 (m, 1H), 4.01-4.14 (m, 2H), 3.69 (d, J=14.08 Hz, 1H), 3.58 (t,J=4.69 Hz, 4H), 3.26 (d, J=14.28 Hz, 1H), 3.12 (s, 3H), 3.00 (dd,J=15.16, 10.47 Hz, 1H), 2.63-2.86 (m, 5H), 2.51-2.63 (m, 2H), 2.51-2.63(m, 2H), 2.34-2.48 (m, 5H), 2.11-2.24 (m, 2H), 2.04-2.11 (m, 1H),1.75-2.03 (m, 6H), 1.59-1.72 (m, 1H), 1.46 (d, J=7.24 Hz, 3H), 1.39 (t,J=13.20 Hz, 1H), 1.03 (d, J=6.65 Hz, 3H). MS (ESI, +ve ion) m/z 750.3(M+1)⁺.

Example 1000132-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-7′-yl)-N,N-dimethylacetamide

N-Butyllithium solution (1.6 M in hexane, 0.83 mL, 1.3 mmol) was addedto a solution of diisopropylamine (0.19 mL, 1.3 mmol) in THF (1.0 mL) at0° C. The solution was stirred at 0° C. for 2 minutes then dimethylacetamide (0.12 mL, 1.3 mmol) was added. The reaction was then stirredat 0° C. for 7 min. Then a solution of(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′,15′-dione13′,13′-dioxide (0.040 g, 0.067 mmol) in THF (1.3 mL) was added andmaintained at 0° C. for 17 min. The reaction was quenched with saturatedammonium chloride solution and acidified with 1 N HCl to pH 2-3 andextracted with EtOAc. The organic phase was washed with brine and driedover anhydrous sodium sulfate and the filtrate was concentrated underreduced pressure to give the crude product that was purified bypreparatory SFC chromatography (CC4 250 mm×21 mm column, Phenomenex; 33g/minute MeOH (2 M ammonia as a modifier)+27 g/minute CO₂ on Thar 200SFC; outlet pressure=100 bar; temperature=40° C.; wavelength=246 nm; 2.0mL injection of 30 mg/mL sample solution of 1:1 DCM:MeOH (2.0 mL) togive2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-7′-yl)-n,n-dimethylacetamide(17 mg, 37% yield) as the first eluting diastereomer. ¹H NMR (400 MHz,DICHLOROMETHANE-d₂) δ 7.71 (d, J=8.4 Hz, 1H), 7.16 (dd, J=2.2, 8.5 Hz,1H), 7.09 (d, J=2.2 Hz, 1H), 7.04-6.98 (m, 2H), 6.97-6.91 (m, 1H), 5.23(br s, 1H), 4.17-4.06 (m, 3H), 3.68 (d, J=14.3 Hz, 1H), 3.58 (d, J=15.3Hz, 1H), 3.23 (d, J=14.3 Hz, 1H), 3.17 (s, 3H), 3.02 (dd, J=9.7, 15.4Hz, 1H), 2.97 (s, 3H), 2.84-2.67 (m, 4H), 2.65-2.54 (m, 1H), 2.46 (quin,J=9.0 Hz, 1H), 2.10-1.97 (m, 2H), 1.96-1.72 (m, 5H), 1.68-1.42 (m, 5H),1.39 (d, J=7.2 Hz, 3H), 1.37-1.35 (m, 1H), 1.35-1.18 (m, 2H), 0.99 (d,J=6.7 Hz, 3H). MS (ESI, +ve ion) m/z 686.2 (M+1)⁺.

Example 100014(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′,11′,12′-TRIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

(1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (200 mg, 0.335 mmol) was dissolved in THF (3.00 mL) andcooled to 0° C. Lanthanum (III) chloride bis(lithium chloride) complexsolution (0.6 M in THF, 0.63 mL, 0.34 mmol) was added to the solutionand the solution was stirred for 45 minutes. The methylmagnesium bromide(3.0 M in diethyl ether solution, 0.50 mL, 1.5 mmol) was added to thesolution and allowed to warm to room temperature overnight. Anotheraliquot of methylmagnesium bromide (3.0 M in diethyl ether solution,0.502 mL, 1.51 mmol) was added and the reaction was stirred for 30minutes to completion then quenched with saturated ammonium chloridesolution. This solution was then acidified to pH 6.5 and then extractedwith EtOAc (2×50 mL). The combined organic layers were then washed withbrine (1×20 mL) and dried over sodium sulfate. The residue was thenpurified by chromatography (silica, 20% to 100% EtOAc (0.3% HOAc):hexanes) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (124 mg, 60% yield) as the second eluting diastereomer.MS (ESI, +ve ion) m/z 613.1 (M+1)⁺.

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-7′,11′,12′-TRIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-Chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (30 mg, 0.049 mmol) was dissolved in tetrahydrofuran(1.0 mL) and cooled to 0° C. Sodium hydride (60% dispersion, 20 mg, 0.49mmol) was then added and the resulting slurry was stirred for 20minutes. The methyl iodide (0.031 mL, 0.49 mmol) was then added and thereaction mixture was stirred for 2.5 hours while slowly warming to roomtemperature. Another aliquot of sodium hydride (60% dispersion, 20 mg,0.49 mmol) and methyl iodide (0.031 mL, 0.49 mmol) was added and thereaction was stirred for an additional 3.5 h to completion. The reactionwas then quenched with dropwise addition of satd. ammonium chlorideaddition and the mixture was extracted with EtOAc (2×50 mL). Thecombined organic layers were then washed with brine (1×20 mL) and driedover sodium sulfate. The crude product was purified by chromatography(silica, 0 to 50% EtOAc/hexanes) to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide. (29 mg, 95% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.89(s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.27 (dd, J=2.1, 8.5 Hz, 1H), 7.17 (d,J=2.0 Hz, 1H), 7.03 (dd, J=1.5, 8.1 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H),6.79 (s, 1H), 5.72 (dd, J=3.2, 9.3 Hz, 1H), 5.65-5.55 (m, 1H), 4.16-4.08(m, 1H), 4.07-3.94 (m, 2H), 3.69 (d, J=14.7 Hz, 1H), 3.59 (d, J=14.3 Hz,1H), 3.24 (d, J=14.3 Hz, 1H), 3.08 (dd, J=9.6, 14.7 Hz, 1H), 2.94 (s,3H), 2.84-2.62 (m, 2H), 2.36-1.60 (m, 12H), 1.43-1.36 (m, 1H), 1.33 (d,J=7.2 Hz, 3H), 1.30 (s, 3H), 0.96 (d, J=6.7 Hz, 3H). MS (ESI, +ve ion)m/z 627.2 (M+1)⁺.

Example 100015(2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-22′,1″-naphthalen]-15′-one13′,13′-dioxide or(2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-22′,1″-naphthalen]-15′-one13′,13′-dioxide

Step 1:(1S,3′R,6′R,8′E,11′S,12′R)-6-CHLORO-11′,12′-DIMETHYL-7′-METHYLIDENE-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

A solution of methyltriphenylphosphonium bromide (1.80 g, 5.0 mmol) inTHF (15 mL) was cooled to 0° C. N-butyllithium solution (2.5 M inhexanes, 1.8 mL, 4.5 mmol) was added dropwise and the solution wasstirred at 0° C. for 10 minutes. The solution was added dropwise to asolution of(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′,15′-dione13′,13′-dioxide (0.30 g, 0.50 mmol) in THF (6.0 mL), cooled in ice bath,until the yellow color persisted. The solution was stirred at 0° C. for12 min. The reaction mixture was added to stirred ice water (20 mL) andacidified with 1 N HCl to pH 2-4. The organic phase was separated andthe aqueous was extracted with EtOAc (50 mL). The organic phase waswashed with brine and dried over magnesium sulfate. The filtrate wasconcentrated to give crude product. The compound was purified bychromatography (silica, 0 to 50% EtOAc (0.3% HOAc:hexanes) to give(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (290 mg, 97% yield). MS (ESI, +ve ion) m/z 595.2 (M+H)⁺.

Step 2:(1S,3′R,6′R,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′-(HYDROXYMETHYL)-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^(3,6).0^(19,24)]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

The AD-Mix-alpha mixture (640 mg, 0.43 mmol) was dissolved in a mixtureof tert-butanol (10.0 mL) and water (10.0 mL) and cooled to 0° C.(1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (255 mg, 0.428 mmol) was added and the reaction mixturewas warmed slowly to room temperature overnight. Another 5.0 mL oft-BuOH was added to homogenize the mixture. The reaction was stirredovernight. Another 320 mg of AD-Mix-alpha mixture was added and thereaction was stirred for an additional three days. The reaction wasquenched by adding 575 mg of sodium sulfite at 0° C. and stirring for 45minutes. The mixture was then extracted with EtOAc (2×25 mL). Thecombined organic layers were washed with brine (1×20 mL) and dried oversodium sulfate. The crude product was then purified by chromatography(silica, 0 to 100% EtOAc (+0.3% HOAc):heptanes) to give(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (31 mg, 12% yield). MS (ESI, +ve ion) m/z 629.2 (M+H)⁺.

Step 3:(1S,3′R,6′R,11′S,12′R)-7′-((2-BROMOETHOXY)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE

(1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (30.0 mg, 0.048 mmol) was dissolved in THF (1.0 mL) andcooled to 0° C. Sodium hydride (60% dispersion, 19.0 mg, 0.48 mmol) wasadded and the resulting slurry was stirred for ten minutes, then2-bromoethyl trifluoromethanesulfonate (Ark Pharm Inc.) (61 mg, 0.24mmol) was added and the reaction was allowed to slowly warm to roomtemperature over 45 minutes. The reaction was then quenched with slowaddition of water (5 mL) and the mixture was extracted (2×25 mL) withethyl acetate. The combined organic layers were washed with brine (1×15mL) and then dried over magnesium sulfate. The residue was then purifiedby chromatography (silica, 0 to 50% EtOAc (+0.3% HOAc): hexanes) to give(1S,3′R,6′R,11′S,12′R)-7′-((2-bromoethoxy)methyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (25 mg, 71% yield). MS (ESI, +ve ion) m/z 739.1 (M+H)⁺.

Step 4:(2S,3′R,6′R,11′S,12′R,22′S)-6″-CHLORO-11′,12′-DIMETHYL-3″,4″-DIHYDRO-2″H,15′H-DISPIRO[1,4-DIOXANE-2,7′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIENE-22′,1″-NAPHTHALEN]-15′-ONE13′,13′-DIOXIDE OR(2R,3′R,6′R,11′S,12′R,22′S)-6″-CHLORO-11′,12′-DIMETHYL-3″,4″-DIHYDRO-2″H,15′H-DISPIRO[1,4-DIOXANE-2,7′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIENE-22′,1″-NAPHTHALEN]-15′-ONE13′,13′-DIOXIDE

(1S,3′R,6′R,11′S,12′R)-7′-((2-Bromoethoxy)methyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one13′,13′-dioxide (25.0 mg, 0.034 mmol) was then dissolved in DMF (0.5 mL)and sodium hydride (60% dispersion, 19 mg, 0.48 mmol) was added. Thismixture was then heated to 85° C. for 10 minutes. The reaction mixturewas then cooled to room temperature and quenched with dropwise additionof water (5 mL). This mixture was extracted with ethyl acetate (2×20mL). The combined organic layers were washed with 1 N LiCl solution(1×15 mL) and brine (1×10 mL) and dried over magnesium sulfate. Thecrude product was the purified by chromatography (silica, 0 to 50% EtOAc(+0.3% HOAc): hexanes) to give(2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″h,15′h-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-22′,1″-naphthalen]-15′-one13′,13′-dioxide or(2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″h,15′h-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-22′,1″-naphthalen]-15′-one13′,13′-dioxide (14 mg, 45% yield). ¹H NMR (400 MHz, MeOH) δ 7.73 (d,J=8.4 Hz, 1H), 7.17 (dd, J=2.2, 8.4 Hz, 1H), 7.13-7.08 (m, 2H), 7.02 (d,J=1.6 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 4.08 (s, 2H), 4.06-4.01 (m, 1H),3.76 (d, J=11.9 Hz, 2H), 3.73-3.59 (m, 4H), 3.58-3.49 (m, 1H), 3.46-3.38(m, 1H), 3.23-3.15 (m, 1H), 3.10 (dd, J=9.1, 15.4 Hz, 1H), 2.86-2.68 (m,2H), 2.62-2.50 (m, 1H), 2.11-2.03 (m, 1H), 1.96-1.84 (m, 3H), 1.76-1.51(m, 7H), 1.49-1.40 (m, 1H), 1.36 (d, J=7.0 Hz, 3H), 1.34-1.27 (m, 2H),1.23-1.19 (m, 2H), 1.01 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 657.2(M+H)⁺.

Example 100017(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a cooled (−78° C.) solution of 4-(but-3-yn-1-yl)morpholine (0.163 g,1.171 mmol) in tetrahydrofuran (3 mL) was added 2.5 M butyllithiumsolution in toluene (0.400 mL, 1.00 mmol) dropwise via syringe. After 45min, a solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (0.100 g, 0.167 mmol) in THF (1 mL) was added dropwise.After 1 h, the reaction was quenched with saturated NH₄Cl (3 mL) and themixture was warmed to room temperature. The mixture was extracted withdichloromethane (3×) and the combined organic layers were washed withbrine and dried over Na₂SO₄. The solution was filtered and the filtratewas concentrated under reduced pressure to give an orange oil. The crudematerial was purified by preparative SFC (Waters Thar 200; Cyano Column(21.1×250 mm, 5 μm) with 18% methanol (20 mM NH₃), 82% carbon dioxide;flow rate=95 mL/min, column temperature=40° C., pressure=100 bar,detection at 220 nm) to give the first eluting diastereomer,(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (32 mg, 26%) as a white solid. ¹H NMR (400 MHz, CD₂Cl₂)δ 7.72 (d, J=8.41 Hz, 1H), 7.13-7.24 (m, 2H), 7.09 (d, J=1.96 Hz, 1H),6.83-6.96 (m, 2H), 6.25-6.41 (m, 1H), 5.75 (d, J=15.26 Hz, 1H), 4.38 (d,J=15.06 Hz, 1H), 4.29 (q, J=7.37 Hz, 1H), 3.97-4.13 (m, 2H), 3.69 (d,J=14.08 Hz, 1H), 3.58 (t, J=4.69 Hz, 4H), 3.26 (d, J=14.28 Hz, 1H), 3.00(dd, J=15.26, 10.37 Hz, 1H), 2.47-2.87 (m, 7H), 2.29-2.46 (m, 5H),1.80-2.21 (m, 9H), 1.61-1.72 (m, 1H), 1.44 (d, J=7.24 Hz, 3H), 1.33-1.41(m, 1H), 1.03 (d, J=6.85 Hz, 3H). MS (ESI, +ve ion) m/z 736.2 (M+1)⁺.

Example 100018(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a cooled (−78° C.) solution of 4-(prop-2-yn-1-yl)morpholine (0.170mL, 1.35 mmol, Ark Pharm, Inc.) in tetrahydrofuran (3 mL) was addedbutyllithium solution (2.5 M in toluene, 0.500 mL, 1.25 mmol) dropwisevia syringe. After 45 min a solution of(1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (0.100 g, 0.167 mmol) in THF (1 mL) was added dropwise.After 1 h, the reaction was quenched with saturated NH₄Cl (3 mL) and themixture was warmed to room temperature. The mixture was extracted withDCM (3×) and the combined organic layers were washed with brine anddried over Na₂SO₄. The solution was filtered and the filtrate wasconcentrated under reduced pressure to give a yellow oil. The crudematerial was purified using preparative SFC (Premier (2×25 cm); 50%methanol/CO₂, 100 bar; 50 mL/min, 254 nm) to give the first elutingisomer,(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (40 mg, 33% yield) as a solid. ¹H NMR (400 MHz, CD₂Cl₂)δ 7.71 (d, J=8.41 Hz, 1H), 7.12-7.23 (m, 2H), 7.09 (d, J=2.15 Hz, 1H),6.84-6.97 (m, 2H), 6.22-6.40 (m, 1H), 5.78 (d, J=14.87 Hz, 1H), 4.25 (d,J=14.67 Hz, 2H), 4.07 (s, 2H), 3.70 (d, J=14.28 Hz, 1H), 3.59-3.66 (m,4H), 3.56 (s, 2H), 3.25 (d, J=14.08 Hz, 1H), 3.02 (dd, J=15.16, 10.47Hz, 1H), 2.67-2.89 (m, 2H), 2.51-2.65 (m, 5H), 2.33-2.49 (m, 1H),2.02-2.16 (m, 4H), 1.76-2.01 (m, 7H), 1.62-1.73 (m, 1H), 1.43 (d, J=7.04Hz, 3H), 1.34-1.41 (m, 1H), 1.04 (d, J=6.46 Hz, 3H). MS (ESI, +ve ion)m/z 722.2 (M+1)⁺.

Example 100019(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide or(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

To a solution of diisopropylamine (1.183 mL, 8.44 mmol) intetrahydrofuran (4.22 mL) at 0° C. was added butyllithium (2.5 M inhexanes, 3.38 mL, 8.44 mmol) for 3 minutes. The solution was then cooledto −78° C. 4-Methyl-morpholin-3-one (0.887 mL, 8.44 mmol) was addeddropwise and the solution was allowed to stir for 1 hour.(1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (0.252 g, 0.422 mmol) in a solution of 0.5 mL of THF wasadded dropwise. Upon completion, saturated ammonium chloride aqueoussolution was added. 1 N HCl was added until the pH reached 2-3 and thesolution was extracted with EtOAc. The organic extract was washed withsaturated NaCl, dried over Na₂SO₄, filtered and concentrated in vacuo.The crude product was adsorbed onto a plug of silica gel andchromatographed through a Biotage SNAP Ultra silica gel column (50 g),eluting with a gradient of 10% to 100% EtOAc:EtOH (3:1) in hexane with0.5% AcOH. The material was further purified by preparative SFC using aMe-sulfone achiral column (21×150 mm, 5 μm), 60% methanol with 20 mMNH₃, flow rate 60 mL/min, column temperature 40° C., pressure 100 bar,detection at 220 nm. The third isomer to elute was isolated to give(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one.¹H NMR (400 MHz, DMSO-d₆) δ 0.92 (d, J=6.06 Hz, 3H) 1.02 (br. s., 2H)1.36 (t, J=12.72 Hz, 1H) 1.61 (br. s., 3H) 1.87 (br. s., 3H) 1.92-2.13(m, 3H) 2.25 (d, J=7.63 Hz, 1H) 2.62-2.79 (m, 2H) 2.84 (s, 3H) 2.86-3.06(m, 3H) 3.29 (br. s., 1H) 3.55 (d, J=13.50 Hz, 1H) 3.71 (br. s., 1H)3.79-4.01 (m, 4H) 4.10 (d, J=13.30 Hz, 1H) 4.26 (br. s., 1H) 5.33 (br.s., 1H) 5.71 (d, J=15.45 Hz, 1H) 6.17 (br. s., 1H) 6.67-6.84 (m, 1H)6.98-7.41 (m, 4H) 7.65 (d, J=8.61 Hz, 1H). MS (ESI, +ve ion) m/z 712.2(M+1)⁺.

Example 1000201-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamideor1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamide

To a solution of N,N-dimethylmethanesulfonamide (206 mg, 1.68 mmol) in2-methyltetrahydrofuran (4 mL) at 0° C. was added n-butyllithium (1.6 Min hexanes, 0.67 mL, 1.7 mmol), and the reaction was stirred at 0° C.for 5 min.(1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (100 mg, 0.167 mmol) in 2-methyltetrahydrofuran (1 mL)was added at low temperature and after 15 min quenched with aqueoussaturated NH₄Cl (50 mL), brine (50 mL) and EtOAc (100 mL). The organiclayer was separated, dried (Na₂SO₄), filtered and concentrated ontosilica. Purification by silica gel chromatography (0 to 100% EtOAc (0.3%AcOH) in heptane afforded1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamideand1-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamide(70 mg, 0.10 mmol, 58% yield) as a mixture of isomers. The mixture wasthen purified by preparatory SFC chromatography (column: Welko-O1 250mm×21 mm column, mobile phase: 65:35 (A:B) isocratic, A: liquid CO₂, B:methanol (20 mM NH₃), flow rate: 70 g/min, column temperature: 40° C.,detection: UV at 220 nm), and the first eluting isomer1-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamideOR1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamide(10 mg, 0.014 mmol, 8% yield) was isolated. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.69 (d, J=8.41 Hz, 1H), 7.17 (dd, J=2.25, 8.51 Hz, 1H),7.09 (d, J=2.15 Hz, 1H), 6.94 (s, 2H), 6.87 (s, 1H), 5.68-5.80 (m, 2H),4.00-4.22 (m, 4H), 3.67-3.83 (m, 2H), 3.57 (br d, J=14.48 Hz, 1H),3.20-3.32 (m, 2H), 3.05-3.16 (m, 1H), 2.96 (s, 6H), 2.89-2.93 (m, 1H),2.69-2.83 (m, 2H), 2.38-2.50 (m, 1H), 2.03-2.17 (m, 3H), 1.85-2.02 (m,3H), 1.72-1.84 (m, 2H), 1.58-1.70 (m, 2H), 1.46 (d, J=7.24 Hz, 3H),1.32-1.41 (m, 1H), 1.06 (d, J=6.06 Hz, 3H). One exchangeable proton wasnot observed. MS (ESI, +ve ion) m/z 720.2 (M+H)⁺.

Table 2 lists compounds prepared by the General Methods outlined in thepresent specification.

TABLE 2 Examples Prepared by the General Methods MS Data Exam- (M + 1)⁺ple Unless Num- Noted ber Structure Name Otherwise 100001

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 643.2 100002

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 698.2 100003

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 690.2 100004

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 691.2 100005

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo [14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(2-methoxyethyl)-N-methylacetamide 742.2 100006

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.2 100007

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′,11′,12′-trimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 100008

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo [14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methyl-N-(2-methyl-2-propanyl)acetamide 762.3 100009

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methylacetamide 684.2 100010

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 100011

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 805.3 100012

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 750.3

100013

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N-dimethylacetamide 686.2 100014

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 627.2 100015

(2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′- dioxideOR (2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′- dioxide657.2 100016

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 613.1 100017

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 736.2

100018

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 722.2

100019

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4- methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4- methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4- methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4- methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 712.2

100020

1-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylmethanesulfonamide OR1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylmethanesulfonamide720.2 100021

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 602.9

100022

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 603.0

100023

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 587.2 100024

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′- methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 587.3 100025

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′-(1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′-(1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 611.0

100026

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′-(1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′-(1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 611.0

100027

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene]-7′-carbonitrile 13′,13′-dioxide OR(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene]-7′-carbonitrile 13′,13′-dioxide 598.0

100028

(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 599.2

100029

(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 599.2

100030

(1S,3′R,6′R,7′R,8′E,12′S)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 599.2

100031

(1S,3′R,6′R,7′S,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,12′R)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,12′R)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 601.2

100032

(1S,3′R,6′R,7′R,8′E,12′S)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,12′S)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-7′-hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetra- cyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 599.2

100033

(1S,3′R,6′R,7′S,8′S,13′R)-6-chloro-7′-hydroxy-7′,13′-dimethyl-3,4-dihydro- 2H,16′H-spiro[naphthalene-1,23′-[21]oxa[14]thia[1,15] diazapenta- cyclo[15.7.2.0~3,6~.0~8,10~.0~20,25~]hexacosa[17,19,25] trien]-16′-one 14′,14′-dioxide OR(1S,3′R,6′R,7′S,8′S,13′R)-6-chloro-7′-hydroxy-7′,13′-dimethyl-3,4-dihydro- 2H,16′H-spiro[naphthalene-1,23′-[21]oxa[14]thia[1,15] diazapenta- cyclo[15.7.2.0~3,6~.0~8,10~.0~20,25~]hexacosa[17,19,25] trien]-16′-one 14′,14′-dioxide OR(1S,3′R,6′R,7′R,8′R,10′R,13′R)-6-chloro-7′-hydroxy-7′,13′-dimethyl-3,4-dihydro- 2H,16′H-spiro[naphthalene-1,23′-[21]oxa[14]thia[1,15] diazapenta- cyclo[15.7.2.0~3,6~.0~8,10~.0~20,25~]hexacosa[17,19,25]trien]-16′-one 14′,14′-dioxide OR(1S,3′R,6′R,7′R,8′R,10′R,13′R)-6-chloro-7′-hydroxy-7′,13′-dimethyl-3,4-dihydro- 2H,16′H-spiro[naphthalene-1,23′-[21]oxa[14]thia[1,15] diazapentacyclo[15.7.2.0~3,6~.0~8,10~.0~20,25~]hexacosa[17,19,25]trien]-16′-one 14′,14′-dioxide 613.2

100034

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 629.0 100035

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 631.1

100036

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(hydroxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 631.1

100037

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl-7′-methoxy-7′-(methoxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl-7′-methoxy-7′-(methoxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 659.1

100038

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl-7′-methoxy-7′-(methoxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl-7′-methoxy-7′-(methoxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 659.1

100039

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(methoxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(methoxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 645.1

100040

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(methoxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(methoxymethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 645.1

100041

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl-7′-(hydroxymethyl)-7′-methoxy-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl-7′-(hydroxymethyl)-7′-methoxy-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 645.1

100042

ethyl (((1S,3′R,6′R,7′S,12′R)-6-chloro-7′-(2-ethoxy-2-oxoethoxy)-12′-ethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)methoxy)acetate OR ethyl(((1S,3′R,6′R,7′R,12′R)-6-chloro-7′-(2-ethoxy-2-oxoethoxy)-12′-ethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)methoxy)acetate 803.1

100043

(2S,3′R,6′R,12′R,22′S)-6″-chloro-12′- ethyl-3″,4″-dihydro-2″H,6H,15′H-dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-22′,1″-naphthalene]-6,15′-dione 13′,13′-dioxide OR(2R,3′R,6′R,12′R,22′S)-6″-chloro-12′- ethyl-3″,4″-dihydro-2″H,6H,15′H-dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-22′,1″-naphthalene]-6,15′-dione 13′,13′-dioxide 671.0

100044

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(trifluoromethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(trifluoromethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13-dioxide 667.0

100045

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(trifluoromethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(trifluoromethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.3 100046

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(trifluoromethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(trifluoromethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.3 100047

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(trifluoromethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′-ethyl-7′-hydroxy-7′-(trifluoromethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13 ′-dioxide 667.0

100048

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 615.2

100049

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 615.2

100050

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetonitrile OR ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetonitrile 638.3 100051

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetonitrile OR ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetonitrile 638.2 100052

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 631.2 100053

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 631.3 100054

(3′R,4S,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-4,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalene]- 2,15′-dione13′,13′-dioxide OR (3′R,4R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-4,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalene]-2,15′-dione13′,13′-dioxide 657.3

100055

(3′R,4R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-4,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalene]- 2,15′-dione13′,13′-dioxide OR (3′R,4S,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-4,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalene]- 2,15′-dione13′,13′-dioxide 657.3

100056

(1S,3′R,6′R,7′S,11′S,13′S,14′R)-6-chloro-7′-hydroxy-13′,14′-dimethyl-3,4-dihydro-2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta-cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~]octacosa[9,18,20,26]tetraen]-17′-one 15′,15′-dioxide OR(1S,3′R,6′R,7′R,11′S,13′S,14′R)-6-chloro-7′-hydroxy-13′,14′-dimethyl-3,4-dihydro-2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta-cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~] octacosa[9,18,20,26]tetraen]-17′-one 15′,15′-dioxide 639.1 100057

(1S,3′R,6′R,7′S,11′R,13′S,14′R)-6-chloro-7′-hydroxy-13′,14′-dimethyl-3,4-dihydro-2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta-cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~]octacosa[9,18,20,26]tetraen]-17′-one 15′,15′-dioxide 639.1 100058

(1S,3′R,6′R,7′R,11′S,13′S,14′R)-6-chloro-7′-hydroxy-13′,14′-dimethyl-3,4-dihydro-2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta-cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~]octacosa[9,18,20,26]tetraen]-17′-one 15′,15′-dioxide 639.0 100059

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methylpropanenitrile OR2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2- methylpropanenitrile 666.3100060

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2- methylpropanenitrile OR2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2- methylpropanenitrile 666.3100061

methyl (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carboxylate 13′,13′-dioxide OR methyl(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carboxylate 13′,13′-dioxide 657.3

100062

(1S,3′R,6′R,7′S,11′R,13′S,14′R)-6-chloro-7′-hydroxy-13′,14′-dimethyl-3,4-dihydro-2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta-cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~] octacosa[18,20,26]trien]-17′-one15′,15′-dioxide 641.1 100063

(1S,3′R,6′R,7′S,9′R,11′S,12′R)-6-chloro-9′-(dimethylamino)-7′-hydroxy-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,9′S,11′S,12′R)-6-chloro-9′-(dimethylamino)-7′-hydroxy-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,9′R,11′S,12′R)-6-chloro-9′-(dimethylamino)-7′-hydroxy-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,9′S,11′S,12′R)-6-chloro-9′-(dimethylamino)-7′-hydroxy-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] 657.8

pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100064

(1S,3′R,6′R,7′S,9′R,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,9′S,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,9′R,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,9′S,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 644.2

100065

(1S,3′R,6′R,7′S,9′R,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,9′S,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,9′R,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,9′S,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 644.2

100066

(1S,3′R,6′R,7′S,9′R,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,9′S,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,9′R,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,9′S,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [2.0]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 643.8

100067

diethyl (((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl) (difluoro)methyl)phosphonate ORdiethyl (((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl) (difluoro)methyl)phosphonate 785.2100068

diethyl (((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl) (difluoro)methyl)phosphonate ORdiethyl (((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl) (difluoro)methyl)phosphonate 785.2100069

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(difluoromethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(difluoromethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~.0~19,24~] pentacosa[16,18,24] tetraen]-15′-one13′,13′-dioxide 649.3 100070

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(difluoromethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(difluoromethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 649.3 100071

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(difluoromethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(difluoromethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 663.0 100072

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.1 100073

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.0 100074

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((S)-methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((R)-methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((S)-methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((R)-methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 675.0

100075

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((S)-methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((R)-methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((S)-methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((R)-methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 675.3

100076

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-ethyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 629.3

100077

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylacetamide OR2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 684.2 100078

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide OR2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 684.2 100079

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-ethyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 629.1 100080

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetonitrile OR ((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetonitrile 640.3 100081

((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetonitrile OR ((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetonitrile 640.3 100082

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N-dimethylacetamide 686.3 100083

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-diethylacetamide OR2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-diethylacetamide 712.2

100084

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-diethylacetamide OR2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-diethylacetamide 712.2

100085

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-morpholinyl)-2-oxoethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-morpholinyl)-2-oxoethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.1

100086

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 728.1

100087

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 728.1

100088

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(2-(dimethylamino)ethyl)-7′-hydroxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 672.3 100089

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 726.3

100090

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 726.2

100091

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 712.2

100092

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 712.4

100093

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(2-(3,3-difluoro-1-azetidinyl)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(2-(3,3-difluoro-1-azetidinyl)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 720.2

100094

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(2-(3,3-difluoro-1-azetidinyl)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(2-(3,3-difluoro-1-azetidinyl)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 720.2

100095

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 714.3 100096

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 714.3

100097

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetic acid OR ((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetic acid 658.8 100098

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methylacetamide OR2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methylacetamide 671.9

100099

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N- dimethylmethanesulfonamide OR1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N- dimethylmethanesulfonamide 722.2 100100

1-((1S,3′R,6′R,7′S,1l′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N- dimethylmethanesulfonamide OR1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N- dimethylmethanesulfonamide 722.3 100101

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid 656.8 100102

(3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalen]- 15′-one 13,13-dioxide643.3 100103

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methylacetamide OR2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methylacetamide 671.9

100104

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 692.3 100105

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 692.3 100106

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 696.2

100107

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 711.8 100108

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 711.8 100109

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 695.9

100110

2-methyl-2-propanyl (2R)-2- ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)propanoate OR 2-methyl-2-propanyl (2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)propanoate OR 2-methyl-2-propanyl (2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)propanoate OR 2-methyl-2-propanyl (2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)propanoate 726.8

100111

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N-diethylacetamide OR2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N-diethylacetamide 713.9 100112

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N-diethylacetamide OR2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N-diethylacetamide 713.9 100113

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.3 100114

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.3 100115

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-[1,3]oxathiolan]-15′-one13′,13′-dioxide OR (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-[1,3]oxathiolan]-15′-one13′,13′-dioxide 659.3 100116

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-[1,3]oxathiolan]-15′-one13′,13′-dioxide OR (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-[1,3]oxathiolan]-15′-one13′,13′-dioxide 659.3 100117

(2R)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR(2R)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide 700.4

100118

(2R)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR(2R)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide 700.4

100119

(2R)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR(2R)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide 700.4

100120

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 670.8

100121

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 670.8

100122

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2S)-24(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 670.8

100123

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 670.8

100124

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylpropanamide 697.7

100125

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR(2R)-2-((1S,3′R,6′R,7′R,8′E,1l′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- 698.2

dimethylpropanamide

100126

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] 698.2

tetraen]-7′-yl)-N,N- dimethylpropanamide

100127

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 639.3 100128

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.4

100129

(2S,3′R,4S,6′R,11′S,12′R,22′S)-6″-chloro-4,11′,12′-trimethyl-3,3″,4,4″-tetrahydro-2″H,5H,15′H-dispiro[furan-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-22′,1″-naphthalene]-5,15′-dione 13′,13′-dioxide AND(2R,3′R,4S,6′R,11′S,12′R,22′S)-6″-chloro-4,11′,12′-trimethyl-3,3″,4,4″-tetrahydro-2″H,5H,15′H-dispiro[furan-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-22′,1″-naphthalene]-5,15′-dione 13′,13′-dioxide 669.2

100130

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 639.0 100131

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 639.2 100132

(2S,3′R,6′R,8′E,11′S,12′R,22′S)-6″- chloro-11′,12′-dimethyl-3″,4,4″,5-tetrahydro-2″H,3H,15′H- dispiro[furan-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene-22′,1″-naphthalen]- 15′-one 13′,13′-dioxide AND(2R,3′R,6′R,8′E,11′S,12′R,22′S)-6″- chloro-11′,12′-dimethyl-3″,4,4″,5-tetrahydro-2″H,3H,15′H- dispiro[furan-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 639.3 100133

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 645.2 100134

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-3″-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-3″-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 670.1

100135

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide OR2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 720.2 100136

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-3″-(dimethylamino)-11′,12′-dimethyl-3,4- dihydro-2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-3″-(dimethylamino)-11′,12′-dimethyl-3,4- dihydro-2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 683.2 100137

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 696.2

100138

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((4-methyl-1-piperazinyl)sulfonyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((4-methyl-1-piperazinyl)sulfonyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 777.2

100139

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((4-methyl-1-piperazinyl)sulfonyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((4-methyl-1-piperazinyl)sulfonyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 777.2

100140

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide OR2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide 730.2

100141

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide OR2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide 730.2

100142

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)acetamide OR2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)acetamide 728.3

100143

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)acetamide OR2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)acetamide 728.2 100144

(1S,3′R,6′R,7′R,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.5

100145

(1S,3′R,6′R,7′R,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.5

100146

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.2 100147

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3″-(1-pyrrolidinyl)-3,4- dihydro-2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3″-(1-pyrrolidinyl)-3,4- dihydro-2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 709.1

100148

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.3

100149

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 645.2 100150

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 645.2 100151

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 691.2 100152

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 691.2 100153

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(2-oxo-1,3-oxazolidin-3-yl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(2-oxo-1,3-oxazolidin-3-yl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 728.5 100154

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(2-oxo-1,3-oxazolidin-3-yl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(2-oxo-1,3-oxazolidin-3-yl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 728.5 100155

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-3″- ((2-methoxyethyl)(methyl)amino)-11′,12′-dimethyl-3,4-dihydro- 2H,4″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]- 15′-one 13′,13′-dioxideOR (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-3″-((2-methoxyethyl)(methyl)amino)- 11′,12′-dimethyl-3,4-dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-7′,5″-[1,2]oxazol]- 15′-one 13′,13′-dioxide 727.1 100156

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.3

100157

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-(3-buten-1-yl)-6-chloro-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(3-buten-1-yl)-6-chloro-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 653.0

100158

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-(3-buten-1-yl)-6-chloro-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(3-buten-1-yl)-6-chloro-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 653.0

100159

(2S,3′R,6′R,8′E,11′S,12′R,22′S)-6″- chloro-11′,12′-dimethyl-3″,4,4″,5-tetrahydro-2″H,3H,15′H- dispiro[furan-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide OR(2R,3′R,6′R,8′E,11′S,12′R,22′S)-6″- chloro-11′,12′-dimethyl-3″,4,4″,5-tetrahydro-2″H,3H,15′H- dispiro[furan-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 639.3 100160

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-methoxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-methoxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.4

100161

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.2

100162

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((1-methyl-1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((1-methyl-1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 695.5 100163

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((1-methyl-1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((1-methyl-1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 695.5 100164

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-oxiran]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-oxiran]-15′-one 13′,13′-dioxide 613.2100165

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene]-7′-yl)-N-(2-methoxyethyl)-N- methylmethanesulfonamide OR1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-(2-methoxyethyl)-N- methylmethanesulfonamide 766.2

100166

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-(2-methoxyethyl)-N- methylmethanesulfonamide OR1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-(2-methoxyethyl)-N- methylmethanesulfonamide 766.3

100167

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 741.2

100168

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 741.2

100169

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)methanesulfonamide OR1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)methanesulfonamide 764.2100170

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)methanesulfonamide OR1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)methanesulfonamide 764.2100171

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehyde OR ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehyde 641.5 100172

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N- dimethylethanethioamide OR((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N- dimethylethanethioamide 702.1

100173

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N- dimethylethanethioamide OR((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N- dimethylethanethioamide 702.1

100174

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-4- pyrimidinylacetamide OR2-(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N-4- pyrimidinylacetamide 736.2 100175

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 643.4 100176

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N-dimethylacetamide OR2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)-N,N-dimethylacetamide 700.2

100177

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-hydroxypropyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-hydroxypropyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.2

100178

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-hydroxypropyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-hydroxypropyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.0

100179

(2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide OR(2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide657.2

100180

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11,12-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.0 100181

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.0 100182

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 613.1 100183

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.2 100184

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 645.2 100185

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 678.2 100186

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 679.2 100187

4-(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-2- pyridinecarbonitrile OR4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-2- pyridinecarbonitrile715.3 100188

4-(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-2- pyridinecarbonitrile OR4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-2- pyridinecarbonitrile715.3 100189

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 659.2 100190

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(ethoxymethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(ethoxymethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 659.2 100191

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(6-methoxy-2-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(6-methoxy-2-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.2

100192

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-((2-methoxyethoxy)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-((2-methoxyethoxy)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 689.2 100193

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-((2-methoxyethoxy)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-((2-methoxyethoxy)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 689.2 100194

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((2-(dimethylamino)ethoxy)methyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-((2-(dimethylamino)ethoxy)methyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 702.2 100195

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-((2-(dimethylamino)ethoxy)methyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((2-(dimethylamino)ethoxy)methyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 702.2 100196

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-((2-(dimethylamino)ethoxy)methyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((2-(dimethylamino)ethoxy)methyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 702.2 100197

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-3″-(dimethylamino)-11′,12′-dimethyl-3,4- dihydro-2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-7′,5″-[1,2]oxazol]- 15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-3″-(dimethylamino)-11′,12′-dimethyl-3,4- dihydro-2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 683.2 100198

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 679.2 100199

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 679.2 100200

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 710.2 100201

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-5-yl)-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′- one 13′,13′-dioxide 710.2 100202

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 698.1

100203

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 698.2

100204

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1-methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 698.1

100205

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4- methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4- methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4- methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4- methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 714.1

100206

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 627.2 100207

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-ethyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 627.2 100208

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- propanyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- propanyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 641.2 100209

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-propyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-propyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 641.3

100210

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- propanyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- propanyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 641.2 100211

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 629.3

100212

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 629.3

100213

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-cyclopropyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-cyclopropyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 639.2 100214

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-cyclopropyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-cyclopropyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 639.2 100215

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 627.2 100216

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3″-(4-methyl-1-piperazinyl)-3,4-dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3″-(4-methyl-1-piperazinyl)-3,4-dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide738.0

100217

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.2 100218

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.1 100219

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′,14′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′,14′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.1 100220

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- methylpropyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- methylpropyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 655.2 100221

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-1,2,4-triazol-5-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene- 1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-1,2,4-triazol-5-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 680.2 100222

(1S,3′R,6′S,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-1,2,4-triazol-5-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-1,2,4-triazol-5-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 680.2 100223

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 681.2 100224

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- methylpropyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- methylpropyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 655.2 100225

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 659.2 100226

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 681.2

100227

(2r,3′R,5R,6′R,11′S,12′R,22′S)-6″-chloro-5-(dimethylamino)-11′,12′-dimethyl- 3″,4″-dihydro-2″H,15′H-dispiro[1,3-dioxane-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-22′,1″-naphthalen]- 15′-one 13′,13′-dioxide AND(2s,3′R,5S,6′R,11′S,12′R,22′S)-6″-chloro-5-(dimethylamino)-11′,12′-dimethyl- 3″,4″-dihydro-2″H,15′H-dispiro[1,3-dioxane-2,7′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 700.1 100228

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-oxetan]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-oxetan]-15′-one 13′,13′-dioxide 627.2100229

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-oxetan]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,2″-oxetan]-15′-one 13′,13′-dioxide 627.2100230

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 695.3 100231

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 629.2 100232

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-propyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-propyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 641.2 100233

(2S,3′R,6′R,8′E,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]- 15′-one13′,13′-dioxide OR (2R,3′R,6′R,8′E,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″- dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]-15′-one13′,13′-dioxide 655.2 100234

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-ethyl-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 641.2 100235

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbonitrile 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbonitrile 13′,13′-dioxide 624.1 100236

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7-propyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,115,12′R)-6-chloro-7-methoxy-11′,12′-dimethyl-7′-propyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 655.2 100237

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbonitrile 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbonitrile 13′,13′-dioxide 624.1 100238

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 719.3

100239

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-4-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-4-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 666.3 100240

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((trimethylsilyl)ethynyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((trimethylsilyl)ethynyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.4 100241

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalele-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 690.3 100242

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 690.3 100243

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((trimethylsilyl)ethynyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((trimethylsilyl)ethynyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.4 100244

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-ethynyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethynyl-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 623.5 100245

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.3 100246

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 100247

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N- phenylacetamide OR2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N- phenylacetamide 746.3

100248

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N- phenylacetamide OR2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N- phenylacetamide 746.3

100249

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 733.4

100250

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3 100251

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3 100252

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.2 100253

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15 ′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.3 100254

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24~]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 733.3 100255

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-cyano-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)benzamide OR N-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-cyano-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)benzamide 729.2

100256

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)benzamide ORN-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)benzamide 734.2

100257

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 100258

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 100259

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 717.0 100260

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 717.2 100261

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 731.5 100262

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 629.2 100263

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-cyano-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetamide OR N-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-cyano-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetamide 667.2

100264

(2S,3′R,6′R,8′E,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]-15′-one13′,13′-dioxide OR (2R,3′R,6′R,8′E,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]-15′-one13′,13′-dioxide 655.2

100265

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)acetamide ORN-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-7′-yl)acetamide 672.2

100266

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 641.2 100267

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 639.2 100268

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 639.3 100269

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0-19,24~]pentacosa[16,18,24] triene-7′,3″-[1,4]oxazinan]-15′-one 13′,13′-dioxideOR (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-7′,3″-[1,4] oxazinan]-15′-one 13′,13′-dioxide656.2 100270

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 679.2 100271

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)methyl methanesulfonate OR((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)methyl methanesulfonate 709.1

100272

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4-morpholinylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetamide OR N-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)acetamide 741.2 100273

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-propen-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 641.3 100274

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.3 100275

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.3 100276

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.3 100277

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2- methoxyethyl)-N-methylacetamide OR2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide 728.2

100278

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 691.2 100279

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 679.2 100280

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 744.3

100281

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2- (dimethylamino)ethyl)-N- methylacetamide OR2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2- (dimethylamino)ethyl)-N- methylacetamide 741.2100282

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2- (dimethylamino)ethyl)-N- methylacetamide OR2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2- (dimethylamino)ethyl)-N- methylacetamide 741.3100283

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)methyl methanesulfonate OR((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-7′-yl)methyl methanesulfonate 709.1 100284

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 744.3

100285

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamideOR (2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamideOR (2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamideOR (2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide714.2 100286

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamideOR (2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamideOR (2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamideOR (2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide714.2

100287

methyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)acetate 671.2 100288

methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)acetate 671.2 100289

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamideOR (2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamideOR (2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylacetamideOR (2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] 700.3

pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamide

100290

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamideOR (2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamideOR (2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamideOR (2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamide700.3

100291

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 627.3100292

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 100293

1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N- dimethylmethanesulfonamide OR1-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N- dimethylmethanesulfonamide 720.2 100294

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-(dimethylamino)-1-propyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-(dimethylamino)-1-propyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 680.3

100295

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-(dimethylamino)-1-propyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-(dimethylamino)-1-propyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 680.5

100296

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 100297

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-(3,3-difluoro-1-azetidinyl)-2-oxoethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 732.2 100298

(3-methyl-3-oxetanyl)methyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetate OR (3-methyl-3-oxetanyl)methyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetate 741.2

100299

(3-methyl-3-oxetanyl)methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetate OR (3-methyl-3-oxetanyl)methyl((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetate 741.2

100300

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7,11′,12′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- ((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 753.3 100301

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 629.4 100302

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 7′,11′,12′-trimethyl-7′-(4-morpholinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 7′,11′,12′-trimethyl-7′-(4-morpholinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.5

100303

(1R,2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro-2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylcarbonyl)-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[cyclopropane-1,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide OR(1R,2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro-2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylcarbonyl)-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[cyclopropane-1,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide779.3

100304

(1R,2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro-2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylcarbonyl)-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[cyclopropane-1,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalen]- 15′-one 13′,13′-dioxideOR (1R,2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro-2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylcarbonyl)-11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[cyclopropane-1,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide779.3

100305

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)-2-oxoethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 781.2 100306

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid 671.2 100307

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid 671.2 100308

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-(dimethylamino)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-(dimethylamino)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.5

100309

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-(dimethylamino)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-(dimethylamino)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.5

100310

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethoxy)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N- dimethylacetamide OR2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethoxy)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N- dimethylacetamide 797.3

100311

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)-2-oxoethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 781.2 100312

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 643.2 100313

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.3

100314

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.3

100315

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((2- propanylsulfonyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((2- propanylsulfonyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 733.3 100316

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((2- propanylsulfonyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((2- propanylsulfonyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 733.3 100317

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-((3R)-3-(dimethylamino)-1- pyrrolidinyl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((3R)-3-(dimethylamino)-1- pyrrolidinyl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14,7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 767.3

100318

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((3R)-3-(dimethylamino)-1- pyrrolidinyl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-((3R)-3-(dimethylamino)-1- pyrrolidinyl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 767.3

100319

(1S,3′R,6′R,7′S,11′S,12′R)-7′-benzyl-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-7′-benzyl-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 691.2

100320

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 722.2

100321

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 690.0 100322

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehyde 655.2 100323

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehyde 655.2 100324

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 707.2

100325

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 707.3 100326

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxy-3-methylbutyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 699.2

100327

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 736.4

100328

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(cis-5-(dimethylamino)-1,3-dioxan-2-yl)-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(cis-5-(dimethylamino)-1,3-dioxan-2-yl)-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 728.3

100329

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-((R)- methylsulfinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-((S)- methylsulfinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-((R)- methylsulfinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-((S)- methylsulfinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 691.3

100330

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-((R)- methylsulfinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-((S)- methylsulfinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-((R)- methylsulfinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-((S)- methylsulfinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 691.3

100331

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.0

100332

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1-propyn- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 653.3 100333

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.3

100334

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.3 100335

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)methyl methanesulfonate OR((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)methyl methanesulfonate 707.2 100336

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4-morpholinylmethyl)-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4-morpholinylmethyl)-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide 712.5

100337

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4-morpholinylmethyl)-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4-morpholinylmethyl)-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide 712.5

100338

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene]-7′-carbaldehyde 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]triene]-7′-carbaldehyde 13′,13′-dioxide 629.2 100339

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-2-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-2-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.0

100340

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-2-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-2-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.0

100341

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 714.3

100342

(1S,3′R,6′R,11′S,12′R)-6-chloro-7′,7′-bis(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 645.2 100343

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(3-methoxy-1-propyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(3-methoxy-1-propyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 681.5

100344

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-hydroxy-1-propyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-hydroxy-1-propyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.2

100345

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-hydroxy-1-propyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-hydroxy-1-propyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.2

100346

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)methyl)-7′-hydroxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)methyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)methyl)-7′-hydroxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)methyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 710.0 100347

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N- diethylacetamide 748.2 100348

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.0 100349

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.0 100350

3-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-1- methylpyridazin-1-ium 705.0 100351

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)ethyl methanesulfonate 757.1 (M +Na) 100352

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(2-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(2-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 720.2 100353

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 724.3

100354

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 724.3

100355

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 742.3

100356

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′S,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 742.3

100357

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.0 100358

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 721.5 (M + Na)

100359

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 721.5 (M + Na)

100360

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.0 100361

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.0 100362

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(6-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(6-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.3 100363

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-methyl- 2-oxobutyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 697.2 100364

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)ethyl methanesulfonate 757.2 (M + Na) 100365

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 100366

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxy-3-methylbutyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 721.3 (M + Na)

100367

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxy-3-methylbutyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 721.3 (M + Na)

100368

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-fluoro-4-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-fluoro-4-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.0 100369

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(2-methoxyethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.2 100370

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-fluoro-4-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-fluoro-4-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.0 100371

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 738.3

100372

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 738.5

100373

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-methyl- 2-oxobutyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 719.3 (M + Na) 100374

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N- cyclopropyl-N- methylacetamide 746.3 100375

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N-(2,2,2- trifluoroethyl)acetamide 788.3 (M +Na) 100376

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 753.3 (M + Na) 100377

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N-(2-(4- morpholinyl)ethyl)acetamide 797.3100378

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 643.2 100379

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 659.0 100380

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 724.2 100381

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-(dimethylamino)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 684.3 100382

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-4-piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-4-piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3

100383

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.0 100384

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.2 100385

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.3 100386

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-4-piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-4-piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3

100387

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-4-piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl-4-piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3

100388

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-(1,1-dioxido-4-thiomorpholinyl)-1- propyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-(1,1-dioxido-4-thiomorpholinyl)-1- propyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 770.4

100389

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-(1,1-dioxido-4-thiomorpholinyl)-1- propyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-(1,1-dioxido-4-thiomorpholinyl)-1- propyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 770.3

100390

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(3-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.3 100391

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 690.2 100392

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.2 100393

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-(dimethylamino)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 684.2 100394

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxy-1-propyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxy-1-propyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 653.5

100395

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxy-1-propyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(3-hydroxy-1-propyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 653.3

100396

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(1- (methoxymethyl)cyclopropyl)-N- methylacetamide790.3 (M + Na) 100397

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 653.3 100398

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidiny)methy)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24] 712.4

pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide

100399

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] 712.4

pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide

100400

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] 712.4

diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide

100401

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.2 100402

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(5-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(5-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.0 100403

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(5-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(5-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.0 100404

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxy-2-propanyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxy-2-propanyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.3 100405

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N- cyclopentyl-N- methylacetamide 774.3 (M + Na) 100406

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 714.3

100407

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(6-methyl-3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(6-methyl-3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 690.0 100408

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(6-methyl-3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(6-methyl-3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 690.0 100409

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 736.3

100410

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.2 100411

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 795.2 100412

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.3 100413

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)-2,2-difluoro-N,N-dimethylacetamide OR 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-2,2-difluoro-N,N- dimethylacetamide 720.0 100414

ethyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)(difluoro)acetate OR ethyl((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)(difluoro)acetate 721.0 100415

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-(4-methyl-3-oxo-1-piperazinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 775.3 (M + Na) 100416

ethyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)(difluoro)acetate OR ethyl((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)(difluoro)acetate 721.0

100417

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((2R)-2,4-dimethyl-1-piperazinyl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((2S)-2,4-dimethyl-1-piperazinyl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 789.3 (M + Na)

100418

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-(cyclopentyl(methyl)amino)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 738.3 100419

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-(4-morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 100420

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.0 100421

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(1-piperidinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(1-piperidinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 720.3

100422

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(4-hydroxy-1-butyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(4-hydroxy-1-butyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.4

100423

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(4-methoxy-1-butyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(4-methoxy-1-butyn-1-yl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 695.3

100424

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(1-piperidinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(1-piperidinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 720.3

100425

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 781.4 100426

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 681.3 100427

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 681.3 100428

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 100429

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 781.4 100430

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-(4- methyl-3-oxo-1-piperazinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 753.3 100431

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-(3-(dimethylamino)-3-methyl-1- azetidinyl)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 753.3 100432

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- (tetrahydro-2H-pyran-4-yl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 721.3 100433

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3- (tetrahydro-2H-pyran-4-yl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 721.3 100434

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 677.2 100435

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxypropyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxypropyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 693.2 (M + Na) 100436

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxypropyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxypropyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 693.2 (M + Na) 100437

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-cyclopropyl-2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-cyclopropyl-2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 719.3 (M + Na)100438

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-((2E)-2-buten-1-yl)-6-chloro-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-((2E)-2-buten-1-yl)-6-chloro-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 667.3 100439

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5-methyl-2- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5-methyl-2- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 690.2 100440

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(2-pyridinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(2-pyridinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 728.3

100441

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((2- propanylsulfanyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 723.2 (M + Na) 100442

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2- propanyloxy)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2- propanyloxy)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.3 100443

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-cyclopropyl-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 717.2 (M + Na)100444

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-((2-methoxyethoxy)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-((2-methoxyethoxy)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 687.2

100445

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-((2-methoxyethoxy)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-((2-methoxyethoxy)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 687.2

100446

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- oxopropyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 691.2 (M + Na) 100447

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-methyl-2-buten-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-methyl-2-buten-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 681.2 100448

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 736.3 100449

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-(1-piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.4 100450

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-cyclobutyl-N- methylacetamide 738.2 100451

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((2R)-1- methoxy-2-propanyl)-N- methylacetamide AND2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((2S)- 1-methoxy-2- propanyl)-N-methylacetamide 778.3(M + Na) 100452

(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′- dimethyl-7′,7′-bis(4-morpholinylmethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 783.5 100453

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-(3-(dimethylamino)-3-methyl-1- azetidinyl)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 753.3 100454

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(2- pyridinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 728.3 100455

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(2- pyridinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 710.3 (M − H₂O] 100456

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-(1,1-dioxido-4-thiomorpholinyl)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 798.3 100457

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2- oxobutyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 705.2 (M + Na) 100458

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2- phenylethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 753.2 (M + Na) 100459

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 705.2 100460

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-cyclopropyl-2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-cyclopropyl-2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 697.2

100461

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-cyclopropyl-2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-cyclopropyl-2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 719.3 (M + Na)

100462

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-cyclopropyl-2-methoxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-cyclopropyl-2-methoxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 711.2

100463

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-cyclopropyl-2-methoxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-cyclopropyl-2-methoxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 733.3 (M + Na)100464

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.2 100465

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2- hydroxyethyl)acetamide 682.0 (M − OMe) 100466

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.3 100467

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′,11′,12′-trimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 100468

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 691.2 100469

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 678.2 100470

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxy-3-methyl-3-buten-1-yl)- 7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxy-3-methyl-3-buten-1-yl)- 7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 697.2 100471

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxy-3-methyl-3-buten-1-yl)- 7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxy-3-methyl-3-buten-1-yl)- 7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 697.2 100472

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(2-(dimethylamino)ethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 686.3 100473

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-((1R)-1-methoxyethyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-((1S)-1-methoxyethyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.3 100474

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((3,5-difluorobenzyl)oxy)-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((3,5-difluorobenzyl)oxy)-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 739.2

100475

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-((1R)-1-methoxyethyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-((1S)-1-methoxyethyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 671.3 100476

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-methyl- 2-oxo-3-buten-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 695.3 100477

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′,11′,12′-trimethyl-7′-(tetrahydro-2H- pyran-4-ylmethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 711.3 100478

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((3R)-4-(dimethylamino)-3-methyl-2- oxobutyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((3S)-4-(dimethylamino)-3-methyl-2- oxobutyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 740.3 100479

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((2R)-2,4-dimethyl-1-piperazinyl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((2S)-2,4-dimethyl-1-piperazinyl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.3

100480

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((2S)-2,4-dimethyl-1-piperazinyl)-2- oxoethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((2R)-2,4-dimethyl-1-piperazinyl)-2-oxoethyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 767.3

100481

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethyl-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-ethyl-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 740.3 100482

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((1S)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((1R)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 659.2 100483

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((1R)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide 659.2

100484

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-(3,3-difluoro-1-azetidinyl)ethoxy)- 7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 732.2 100485

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-(4-(2-methoxyethyl)-1-piperazinyl)ethoxy)-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 783.3 100486

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((1S)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((1R)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.3 100487

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((1R)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((1S)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.3 100488

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(4-(4- (methylsulfonyl)-1-piperazinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 827.2 100489

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxy-2-(2-pyridinyl)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxy-2-(2-pyridinyl)ethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro [naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 734.3 100490

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2S)-2-hydroxy-2-(2-pyridinyl)ethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((2R)-2-hydroxy-2-(2-pyridinyl)ethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene- 1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 734.3 100491

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(2- pyridinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 754.2 (M + Na) 100492

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7-((methylsulfonyl)methyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 705.2 100493

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5-(4-morpholinyl)-1-pentyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 750.3 100494

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5-(4-morpholinyl)-1-pentyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 750.3 100495

(2R,3′R,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-15′-oxo-3″,4″-dihydro- 2″H-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalene]-3- carbaldehyde13′,13′-dioxide OR (2R,3S,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-15′-oxo-3″,4″-dihydro- 2″H-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalene]-3- carbaldehyde13′,13′-dioxide OR (2S,3′R,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-15′-oxo-3″,4″-dihydro- 2″H-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalene]-3- carbaldehyde13′,13′-dioxide OR (2S,3S,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-15′-oxo-3″,4″-dihydro- 2″H-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] triene-22′,1″-naphthalene]-3- carbaldehyde13′,13′-dioxide 685.3

100496

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2-propen-1-yloxy)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2-propen-1-yloxy)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 669.2 100497

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1,3- thiazol-2-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1,3- thiazol-2-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 696.0 100498

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 637.4 100499

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 637.3 100500

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4,5-dihydro-1,3-oxazol-2-ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 100501

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1-propyn- 1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 651.2 100502

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-ethynyl-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 637.3 100503

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethynyl-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 637.3 100504

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-ethynyl-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 736.2 100505

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethynyl-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 736.2 100506

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-((3S)-3-methyl-4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 764.2 100507

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(5-(dimethoxymethyl)-3-pyridinyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(5-(dimethoxymethyl)-3-pyridinyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 750.0

100508

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1,3-oxazol-2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.3 100509

N-(2-chloroethyl)-2- ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetamide 754.2 (M + Na) 100510

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(5-(dimethoxymethyl)-3-pyridinyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14,7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(5-(dimethoxymethyl)-3-pyridinyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 750.0

100511

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(5-(dimethoxymethyl)-3-pyridinyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(5-(dimethoxymethyl)-3-pyridinyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 764.2

100512

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 709.2 100513

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 761.0 100514

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(5-(dimethoxymethyl)-3-pyridinyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(5-(dimethoxymethyl)-3-pyridinyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 764.2

100515

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 775.1 100516

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-methyl-1,3-thiazol-4-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 695.8 100517

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-methyl-1,3-thiazol-4-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.0 100518

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(3-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1-propyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 791.3 100519

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-pyrimidinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 743.2 100520

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′- methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide 685.1 100521

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(5-(4- morpholinylmethyl)-3-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(5-(4-morpholinylmethyl)-3-pyridinyl)- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(5-(4- morpholinylmethyl)-3-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(5-(4-morpholinylmethyl)-3-pyridinyl)- 3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 789.2 100522

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1,3- thiazol-2-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1,3- thiazol-2-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 696.0 100523

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((1-methyl-1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.0 100524

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((1-methyl-1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.0 100525

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1,3-thiazol-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.0 100526

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((3-methyl- 2-pyrazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 705.0 100527

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-methyl-1,3-oxazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.2 100528

methyl N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro- 2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)-D-alaninate 778.3 (M + Na)100529

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((5-methyl-1,3-oxazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.2 100530

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.0 100531

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((4R)-4-methyl-5-oxo-4,5-dihydro-1,3-oxazol-2- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((4S)-4-methyl-5-oxo-4,5-dihydro-1,3-oxazol-2- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 724.2 100532

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((4-methyl-2-pyridinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 704.0 100533

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((4-methyl-2-pyridinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 704.0 100534

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5-phenyl-3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(5-phenyl-3- pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 752.2 100535

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(6-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 676.0 100536

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 694.0 100537

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide AND(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 100538

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 708.0 100539

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-chloro-1-methyl-1H-imidazol-5-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-chloro-1-methyl-1H-imidazol-5-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 727.2 100540

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((5-methyl-1,2-oxazol-3-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 100541

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((5-methyl-1,2-oxazol-3-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 100542

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((3-methyl-2-pyridinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 718.0 100543

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-chloro-1-methyl-1H-imidazol-5-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-chloro-1-methyl-1H-imidazol-5-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 713.2 100544

methyl N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)-2- methylalaninate 738.2 (M− OMe) 100545

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((3R)-2- oxotetrahydro-3-furanyl)acetamide AND2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((3S)-2- oxotetrahydro-3-furanyl)acetamide 722.3 (M −OMe) 100546

N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)-2- methylalanine 724.2 (M −OMe) 100547

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((4,4-dimethyl-5-oxo-4,5-dihydro-1,3-oxazol-2-yl)methyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 738.2 100548

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((5-methyl-1,2-oxazol-3-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.0 100549

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((5-oxo-4,5-dihydro-1,3-oxazol-2-yl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.3 100550

methyl N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)glycinate 710.3 (M − OMe)100551

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-chloro-1-methyl-1H-imidazol-5-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-chloro-1-methyl-1H-imidazol-5-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 713.2 100552

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((5-methyl-1,2-oxazol-3-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.0 100553

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2 100554

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(5-((dimethylamino)methyl)-3-pyridinyl)-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 747.2 100555

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,2-dimethyl-1H-imidazol-5-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,2-dimethyl-1H-imidazol-5-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2 100556

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1-methyl-1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2

100557

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(4-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(4-methoxy-3-pyridinyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.2

100558

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-chloro-1-methyl-1H-imidazol-5-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-chloro-1-methyl-1H-imidazol-5-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 727.1 100559

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,2-dimethyl-1H-imidazol-5-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,2-dimethyl-1H-imidazol-5-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2 100560

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-methyl-2-pyridinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 718.0 100561

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((3R)-2- oxotetrahydro-3- furanyl)acetamide OR2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((3S)-2- oxotetrahydro-3-furanyl)acetamide 722.2 (M −OMe) 100562

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((3R)-2- oxotetrahydro-3-furanyl)acetamide OR2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((3S)-2- oxotetrahydro-3-furanyl)acetamide 722.2 (M −OMe) 100563

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((2R)-3,3,3-trifluoro- 2-hydroxypropyl)acetamide AND2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-((2S)-3,3,3- trifluoro-2- hydroxypropyl)acetamide750.2 (M − OMe) 100564

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-2-propen-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.0 100565

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-2-propen-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.0 100566

(1S,3′R,6′R,7′S,8′E,10′S,11′S)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-10′,11′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 717.0 100567

(1S,3′R,6′R,7′S,8′E,10′S,11′S)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-10′,11′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 731.0 100568

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(2-fluoro-2-propen-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.0 100569

(1S,3′R,6′R,7′R,8′E,10′S,11′S)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-10′,11′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 731.0 100570

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((4-(hydroxymethyl)-1,3-oxazol-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 100571

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′- methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide 685.1 100572

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((4-methyl-1,3-oxazol-5-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.8 100573

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((4,5-dimethyl-1,2-oxazol-3-yl)methyl)- 7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 708.0 100574

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((4,5-dimethyl-1,2-oxazol-3-yl)methyl)- 7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 722.0 100575

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-12′-benzyl-6-chloro-7′-methoxy-11′-methyl- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-12′-benzyl-6-chloro-7′-methoxy-11′-methyl- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′S)-12′-benzyl-6-chloro-7′-methoxy-11′-methyl- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12S)-12- benzyl-6-chloro-7′-methoxy-11′-methyl-15′-oxo-3,4-dihydro-2H- 717.5

spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

100576

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3- yloxy)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 789.2 100577

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(1,3-oxazol-2- ylmethyl)acetamide 719.3 (M − OMe)100578

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((4,5-dimethyl-1,2-oxazol-3-yl)methyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 708.0 100579

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-12′-ethyl-7′-methoxy-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-12′-ethyl-7′-methoxy-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 731.2

100580

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-15′-oxo-3,4-dihydro- 2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-15′-oxo-3,4-dihydro- 2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 641.2100581

methyl N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)-D- allothreoninate 754.2 (M− OMe) 100582

methyl (2R)-2- ((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetyl)amino)-3- oxobutanoate AND methyl (2S)-2-((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetyl)amino)-3- oxobutanoate 752.2 (M − OMe)

100583

methyl 2-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-5-methyl-1,3-oxazole-4-carboxylate 766.3 100584

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((4-(hydroxymethyl)-5-methyl-1,3-oxazol-2-yl)methyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 738.2 100585

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′-((4-(methoxymethyl)-5-methyl-1,3-oxazol-2-yl)methyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 752.3 100586

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((4-((dimethylamino)methyl)-5-methyl-1,3-oxazol-2-yl)methyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 765.3 100587

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((5-methyl-4-(4-morpholinylmethyl)-1,3-oxazol-2- yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 807.3 100588

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-12′-benzyl-6-chloro-7′-(hydroxymethyl)-7′- methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-12′-benzyl-6-chloro-7′-(hydroxymethyl)-7′- methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′S)-12′-benzyl-6-chloro-7′-(hydroxymethyl)-7′- methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- 20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′S)-12′-benzyl-6-chloro-7′-(hydroxymethyl)-7′- methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 742.2 (M + Na)

100589

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-7′-yl)acetamide 638.3 (M − OMe) 100590

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 756.2 100591

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2- yl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 779.3 100592

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-((9aR)- octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)ethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 781.2 100593

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-7′,11′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-7′,11′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.2 100594

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 756.2 100595

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′-dimethyl-12′-(2-(4-morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′-dimethyl-12′-(2-(4-morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 100596

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-7′,11′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-7′,11′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 657.2 100597

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′- ethyl-7′-methoxy-7′-((2-(4-morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′- ethyl-7′-methoxy-7-((2-(4-morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 756.2

100598

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-12′-yl)ethyl methanesulfonate OR2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-methoxy-7′,11′-dimethyl-13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-12′-yl)ethyl methanesulfonate 703.3 (M −OMe) 100599

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′-dimethyl-12′-(2-(4-morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′-dimethyl-12′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 726.2 100600

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′-trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene- 1,22′-[20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 614.0 100601

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′-trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′-trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene- 1,22′-[20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 614.0 100602

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-15′-oxo-7′-propoxy-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide 669.3 100603

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-(2-methylpropoxy)- 15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide 683.3 100604

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(2,2,2-trifluoroethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-11′,12′-dimethyl-7′-(2,2,2-trifluoroethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~]pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 711.2 100605

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-ethyl-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethyl-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 641.2

GENERAL SYNTHESIS OF INTERMEDIATES N-Methyl-2-morpholinoethanamine

Step 1: tert-butyl (2-morpholinoethyl)carbamate

A 2-dram vial was charged with di-t-butyldicarbonate (0.459 mL, 2.000mmol), a magnetic stir bar, and indium (III) chloride (4.42 mg, 0.020mmol). 4-(2-Aminoethyl)morpholine (0.262 mL, 2 mmol) was then added tothe stirring solution. After 1 min, the solution was diluted with EtOAc(2 mL). Water (3 mL) was added and the layers were partitioned. Theorganic layer was washed with water (2×5 mL), dried over MgSO₄,filtered, and concentrated to afford tert-butyl(2-morpholinoethyl)carbamate as a clear oil. The material was carriedforward without further purification.

Step 2: N-methyl-2-morpholinoethanamine

A 125 mL three-neck flask with stir bar was heated with a heat gun undervacuum. Under a positive pressure of nitrogen, a reflux condenser wasattached to the middle neck. The flask was charged with tetrahydrofuran(25.00 mL) and lithium aluminium hydride (2 M solution in THF, 0.84 mL,20 mmol), tert-butyl (2-morpholinoethyl)carbamate (0.46 g, 2 mmol) wasadded as a solution in THF (8 mL) and the resulting homogenous mixturewas heated to reflux for 18 h. The reaction mixture was cooled to 0° C.in an ice-water bath and quenched with sodium sulfate decahydrate. Theresulting mixture was filtered through Celite, rinsing with THF.Concentration of the filtrate afforded N-methyl-2-morpholinoethanaminewhich was used without further purification.(3S)-1-Cyclobutyl-3-methylhex-5-ene-2-sulfonamide

Step 1. (R)-pent-4-en-2-yl 4-methylbenzenesulfonate

To a solution of vinyl magnesium bromide (226 g, 1722 mmol, 1.0 M inTHF) was added to CuI (29.5 g, 155 mmol, 0.09 equiv) in THF (200 mL) at−40° C. The reaction mixture was stirred for 30 min followed by a cooledsolution of (R)-2-methyloxirane (100 g, 1722 mmol) in THF (500 mL) wasadded drop wise at the same temperature. The resulting reaction mixturewas stirred at −40° C. for 1 h. After the reaction was completed(monitored by TLC), triethylamine (261 g, 2583 mmol) was added at −40°C. After 30 min, cooled solution of p-toluene sulfonyl chloride (427 g,2238 mmol) in THF (1000 mL) was added slowly to the reaction mixture atsame temperature and stirred for 16 h at ambient temperature. After thereaction was completed (monitored by TLC), the reaction mixture wasquenched with 1.5 N HCl solution until pH 3.0. The resulting reactionmixture was filtered through celite pad, layers were separated and theaqueous layer was re-extracted with ethyl acetate (2×2000 mL). Thecombined organic layers were washed with water (800 mL), brine (500 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified on flash column chromatography (silica gel, 230-400mesh) using 1% to 2% ethyl acetate in petroleum ether to provide(R)-pent-4-en-2-yl 4-methylbenzenesulfonate (207 g, 50% yield) as acolourless liquid. ¹H NMR (300 MHz, Chloroform-d) δ 7.83-7.75 (m, 2H),7.37-7.31 (m, 2H), 5.69-5.52 (m, 1H), 5.09-5.04 (m, 1H), 5.01 (t, J=1.3Hz, 1H), 4.65 (h, J=6.3 Hz, 1H), 2.45 (s, 3H), 2.37-2.22 (m, 2H), 1.26(d, J=6.3 Hz, 3H).

Step 2: (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide

To a stirred solution of N,N-bis(4-methoxybenzyl)methanesulfonamide (207g, 617 mmol) in THF (2000 mL) was added n-BuLi (321 mL, 802 mmol, 2.5 Min hexane) at −78° C. The resulting reaction mixture was stirred for 1 hat same temperature followed by (R)-pent-4-en-2-yl4-methylbenzenesulfonate (206 g, 858 mmol) in THF (400 mL) was addeddropwise at −78° C. The reaction mixture was allowed to warm to ambienttemperature and stirred for 16 h. After the reaction was complete(monitored by TLC), the reaction mixture was quenched with saturatedammonium chloride solution, layers were separated and the aqueous layerwas extracted with ethyl acetate (2×2000 mL). The combined organiclayers were washed with water (1000 mL), brine (600 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography (silica gel, 230-400mesh) using 2% to 4% ethyl acetate in petroleum ether to provide(S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (105 g,42% yield) as a colourless liquid. ¹H NMR (400 MHz, Chloroform-d) δ7.25-7.20 (m, 4H), 6.92-6.85 (m, 4H), 5.70 (ddt, J=17.2, 10.2, 7.1 Hz,1H), 5.12-4.98 (m, 2H), 4.32-4.19 (m, 4H), 3.83 (s, 6H), 2.90-2.80 (m,1H), 2.66-2.55 (m, 1H), 2.27-2.17 (m, 1H), 2.17-2.02 (m, 2H), 1.11 (d,J=6.7, 3H).

Step 3.(3S)-1-cyclobutyl-N,N-bis(4-methoxybenzyl)-3-methylhex-5-ene-2-sulfonamide

To a stirred solution of(S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (40 g, 99mmol) in THF (400 mL) was added n-butyl lithium (86.73 mL, 139 mmol, 1.6M in hexane) at −78° C. The reaction mixture was allowed to stir for 20min at same temperature. (Bromomethyl)cyclobutane (59.1 g, 396 mmol) wasadded dropwise at same temperature and stirred for 30 min. The resultingreaction mixture was allowed to warm to ambient temperature and stirredfor 16 h. After the reaction was complete (monitored by TLC), thereaction mixture was quenched with saturated ammonium chloride solution,layers were separated and the aqueous layer was extracted with ethylacetate (2×400 mL). The combined organic layers were washed with water(100 mL), brine (100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified by flash columnchromatography (silica gel, 230-400 mesh) using 2% to 4% ethyl acetatein petroleum ether as an eluent to provide(3S)-1-cyclobutyl-N,N-bis(4-methoxybenzyl)-3-methylhex-5-ene-2-sulfonamide(33 g, 71% yield) as colourless liquid. ¹H NMR (300 MHz, Chloroform-d) δ7.30-7.16 (m, 4H), 6.92-6.80 (m, 4H), 5.13-4.95 (m, 2H), 4.40-4.20 (m,4H), 3.81 (s, 6H), 2.87-2.63 (m, 2H), 2.16-1.72 (m, 6H), 1.65-1.24 (m,6H), 1.15-0.81 (m, 3H).

Step 4: (3S)-1-cyclobutyl-3-methylhex-5-ene-2-sulfonamide

To a stirred solution of(3S)-1-cyclobutyl-N,N-bis(4-methoxybenzyl)-3-methylhex-5-ene-2-sulfonamide(33 g, 70.0 mmol), anisole (33 mL) and TFA (33 mL) at 0° C. Theresulting reaction mixture was heated to 40° C. for 16 h. After thereaction was complete (monitored by TLC), volatiles were removed undervacuum and the crude was purified by flash column chromatography (silicagel, 230-400 mesh) using 15% to 20% ethyl acetate in petroleum ether asan eluent to yield (3S)-1-cyclobutyl-3-methylhex-5-ene-2-sulfonamidewhich was further purified by HPLC [Column Sunfire C18 (250 mm×19 mm) 5μm, 0.1% formic acid in water and acetonitrile, 90 mg/injection, ELSDdetector, run time 35 min.] to provide(3S)-1-cyclobutyl-3-methylhex-5-ene-2-sulfonamide (10.3 g, 64% yield) asa colourless liquid. MS (ESI, −ve ion) m/z 230 (M−H)⁻. ¹H NMR (400 MHz,DMSO-d₆) δ 6.78 (d, J=9.1 Hz, 2H), 5.73 (tdd, J=12.4, 10.1, 6.5 Hz, 1H),5.05 (tt, J=17.7, 4.5 Hz, 2H), 2.70-2.54 (m, 2H), 2.30 (p, J=7.1 Hz,1H), 2.00 (dq, J=26.6, 7.3 Hz, 4H), 1.90-1.72 (m, 3H), 1.58 (dtt,J=26.6, 17.4, 8.5 Hz, 3H), 0.94 (ddd, J=14.1, 7.1, 2.1 Hz, 3H).

1-(But-2-yn-1-yl)piperazin-2-one

Step 1: tert-butyl 4-(but-2-yn-1-yl)-3-oxopiperazine-1-carboxylate

To a cooled (0° C.) slurry of 60% sodium hydride in mineral oil (0.600g, 15.00 mmol) in THF (40 mL) was added a solution of1-Boc-3-oxopiperazine (2.0 g, 9.99 mmol; Combi-Blocks, San Diego,Calif.) in N, N-dimethylformamide (10 mL). After complete addition thereaction was allowed to warm to room temperature for 30 min. The mixturewas cooled to 0° C. and treated with 1-bromo-2-butyne (1.2 mL, 13.71mmol). The reaction was allowed to warm to rt for 30 min. The reactionwas quenched with saturated NH₄Cl solution, partitioned betweenEtOAc/brine and the aqueous layer was extracted with EtOAc (3×). Thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure to give tert-butyl4-(but-2-yn-1-yl)-3-oxopiperazine-1-carboxylate as a light-brown liquid.

Step 2: 1-(but-2-yn-1-yl)piperazin-2-one

To a room temperature solution of tert-butyl4-(but-2-yn-1-yl)-3-oxopiperazine-1-carboxylate (2.52 g, 9.99 mmol) inDCM (40 mL) was added trifluoroacetic acid (10 mL, 135 mmol) viasyringe. After 1 h the solvent was removed in vacuo and the residue wasdissolved in DCM. The solution was loaded onto an Si-propylsulfonic acid(Silicycle) cartridge eluting with DCM, MeOH then 2 M NH₃ in MeOH togive 1-(but-2-yn-1-yl)piperazin-2-one (1.269 g, 83% yield) as a brownoil. ¹H NMR (400 MHz, CDCl₃) δ 4.20 (q, J=2.41 Hz, 2H), 3.52 (s, 2H),3.42 (t, J=5.48 Hz, 2H), 3.12 (t, J=5.58 Hz, 2H), 1.81 (t, J=2.45 Hz,3H).

The intermediates shown in the following Table 3 were prepared analogousto the method described above for 1-(but-2-yn-1-yl)piperazin-2-one.

TABLE 3 MS Starting Data Material Product Name (M + 1)⁺

1-(2-(2- methoxyethoxy)ethyl)piperazin- 2-one 203.3

1-(2- (dimethylamino)ethyl)piperazin- 2-one 172.1

1-(2-Morpholinoethyl)piperazin-2-one

Step 1: tert-butyl 4-(2-morpholinoethyl)-3-oxopiperazine-1-carboxylate

To a room temperature suspension of 1-boc-3-oxopiperazine (2.0 g, 9.99mmol; Combi-Blocks, San Diego, Calif.), tetrabutylammonium bromide(0.620 g, 1.923 mmol) and potassium hydroxide (1.42 g, 25.3 mmol) in THF(25 mL) was added 4-(2-bromoethyl)morpholine hydrobromide (2.78 g, 10.11mmol; Combi-Blocks, San Diego, Calif.) as a solid. After stirring atroom temperature overnight the mixture was filtered and the filtrate wasevaporated onto silica gel and purified by flash chromatography (Isco,(80 gram)) eluting with 2 M NH₃ in MeOH:CH₂Cl₂ (0:1→1:9) to givetert-butyl 4-(2-morpholinoethyl)-3-oxopiperazine-1-carboxylate (1.923 g,61% yield) as a solid. MS (ESI, +ve ion) m/z 314.3 (M+1)⁺.

Step 2: 1-(2-morpholinoethyl)piperazin-2-one

To a room temperature solution of tert-butyl4-(2-morpholinoethyl)-3-oxopiperazine-1-carboxylate (1.84 g, 5.87 mmol)in DCM (15 mL) was added trifluoroacetic acid (5 mL). After 3 h thesolvent was removed under reduced pressure and the residue was dissolvedin DCM and loaded onto a plug of Si-propylsulfonic acid (Silicycle) andthe plug washed with 1:1 MeOH/DCM to 2 M NH₃ in MeOH/DCM. The fractionscontaining desired product were concentrated under reduced pressure togive 1-(2-morpholinoethyl)piperazin-2-one (1.52 g) as a yellow oil. MS(ESI, +ve ion) m/z 214.1 (M+1)⁺.

(2S,3S)-3-Methyl-1-phenylhex-5-ene-2-sulfonamide and(2R,3S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide

Step 1: (R)-pent-4-en-2-yl 4-methylbenzenesulfonate

To a solution of vinyl magnesium bromide (226 g, 1722 mmol, 1.0 M inTHF) was added to CuI (29.5 g, 155 mmol) in THF (200 mL) at −40° C. Thereaction mixture was stirred for 30 min followed by a cooled solution of(R)-2-methyloxirane (100 g, 1722 mmol) in THF (500 mL) was added dropwise at the same temperature. The resulting reaction mixture was stirredat −40° C. for 1 h. After the reaction was completed (monitored by TLC),triethylamine (261 g, 2583 mmol) was added at −40° C. After 30 min,cooled solution of p-toluene sulfonyl chloride (427 g, 2238 mmol) in THF(1000 mL) was added slowly to the reaction mixture at same temperatureand stirred for 16 h at ambient temperature. After the reaction wascompleted (monitored by TLC), the reaction mixture was quenched with 1.5N HCl solution until pH 3.0. The resulting reaction mixture was filteredthrough celite pad, layers were separated and the aqueous layer wasre-extracted with ethyl acetate (2×2000 mL). The combined organic layerswere washed with water (800 mL), brine (500 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified onflash column chromatography (silica gel, 230-400 mesh) using 1% to 2%ethyl acetate in petroleum ether to provide (R)-pent-4-en-2-yl4-methylbenzenesulfonate (207 g, 50% yield) as a colourless liquid. ¹HNMR (300 MHz, Chloroform-d) δ 7.83-7.75 (m, 2H), 7.37-7.31 (m, 2H),5.69-5.52 (m, 1H), 5.09-5.04 (m, 1H), 5.01 (t, J=1.3 Hz, 1H), 4.65 (h,J=6.3 Hz, 1H), 2.45 (s, 3H), 2.37-2.22 (m, 2H), 1.26 (d, J=6.3 Hz, 3H).

Step 2: (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide

To a stirred solution of N,N-bis(4-methoxybenzyl)methanesulfonamide (207g, 617 mmol, 1.0 equiv) in THF (2000 mL) was added n-BuLi (321 mL, 802mmol, 2.5 M in hexane) at −78° C. The resulting reaction mixture wasstirred for 1 h at same temperature followed by (R)-pent-4-en-2-yl4-methylbenzenesulfonate (206 g, 858 mmol) in THF (400 mL) was addeddropwise at −78° C. The reaction mixture was allowed to warm to ambienttemperature and stirred for 16 h. After the reaction was complete(monitored by TLC), the reaction mixture was quenched with saturatedammonium chloride solution, layers were separated and the aqueous layerwas extracted with ethyl acetate (2×2000 mL). The combined organiclayers were washed with water (1000 mL), brine (600 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography (silica gel, 230-400mesh) using 2% to 4% ethyl acetate in petroleum ether to provide(S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (105 g,42.2% yield) as a colourless liquid. ¹H NMR (400 MHz, Chloroform-d) δ7.25-7.20 (m, 4H), 6.92-6.85 (m, 4H), 5.70 (ddt, J=17.2, 10.2, 7.1 Hz,1H), 5.12-4.98 (m, 2H), 4.32-4.19 (m, 4H), 3.83 (s, 6H), 2.90-2.80 (m,1H), 2.66-2.55 (m, 1H), 2.27-2.17 (m, 1H), 2.17-2.02 (m, 2H), 1.11 (d,J=6.7, 3H).

Step 3:(2S,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamideand (2R,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamide

To a stirred solution of(S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (65 g, 161mmol) in THF (650 mL) was added n-butyl lithium (140.9 mL, 226 mmol, 1.6M in hexane) at −78° C. The reaction mixture was stirred for 20 min atsame temperature. (Bromomethyl)benzene (110 g, 644 mmol) was addeddropwise at same temperature and stirred for 30 min at −78° C. Theresulting reaction mixture was warmed to ambient temperature and stirredfor 1 h. After the reaction was complete (monitored by TLC), thereaction mixture was quenched with saturated ammonium chloride solution,layers were separated and the aqueous layer was extracted with ethylacetate (2×500 mL). The combined organic layers were washed with water(300 mL), brine (100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified by flash columnchromatography (silica gel, 230-400 mesh) using 2% to 4% ethyl acetatein petroleum ether as an eluent to provide(2S,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamideAND (2R,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamide(60.5 g, 76% yield) as a colourless liquid. ¹H NMR (400 MHz,Chloroform-d) δ 7.28-7.14 (m, 7H), 7.02-6.92 (m, 2H), 6.90-6.84 (m, 4H),5.60-5.52 (m, 1H), 5.04-4.82 (m, 2H), 4.54-4.32 (m, 2H), 4.10-3.96 (m,2H), 3.84-3.80 (m, 6H), 3.28-3.12 (m, 2H), 2.98-2.88 (m, 1H), 2.42-2.08(m, 1H), 2.00-1.76 (m, 2H), 1.18-1.04 (m, 3H).

Step 4: (2S,3S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide and (2R,3S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide

To a stirred solution of(2S,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamideAND(2R,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamide(60 g, 122 mmol) in anisole (99 g, 915 mmol) was added TFA (148 g, 1298mmol) at 0° C. The resulting reaction mixture was heated to 40° C. for16 h. After the reaction was completed (monitored by TLC), volatileswere removed under reduced pressure and the crude was purified by flashcolumn chromatography (silica gel, 230-400 mesh) using 15% to 20% ethylacetate in petroleum ether as an eluent to provide(2S,3S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide AND(2R,3S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide (21.5 g, 70% yield) asliquid. MS (ESI, −ve ion) m/z 254.2 (M-1)-. ¹H NMR (400 MHz, DMSO-d₆) δ7.37-7.15 (m, 5H), 6.94-6.86 (m, 2H), 5.62-5.54 (m, 1H), 4.96-4.70 (m,2H), 3.32-3.20 (m, 2H), 2.92-2.80 (m, 1H), 2.49-2.28 (m, 1H), 2.10-1.78(m, 2H), 1.08-0.90 (m, 3H).

(2S,3S)-2,3-Dimethylpent-4-ene-1-sulfonamide

Step 1: meso-2,3-dimethylbutane-1,4-diol

A solution of meso-2,3-dimethylsuccinic acid (50.0 g, 342 mmol) in THF(700 mL) was cooled to 0° C. Lithium aluminum hydride (2.0 M solution intetrahydrofuran, 428.0 mL, 855.0 mmol) was then cannulated into theaddition funnel, and then added into the stirred cooled mixture dropwiseover 15 min. After the addition was completed the reaction was allowedto warm to room temperature and stirred for 12 h under a nitrogenatmosphere. The reaction mixture was quenched with MeOH (350 mL)dropwise at 0° C. and then 20% KOH (150 mL) aqueous solution was addedslowly. The reaction mixture was stirred at 0° C. for 20 min, EtOAc(1000 mL) was added and the organic phase was dried over MgSO₄ filteredand concentrated under reduced pressure to givemeso-2,3-dimethylbutane-1,4-diol (40.0 g, 100% yield) which was used assuch in next step. MS (ESI, +ve ion) m/z 119.2 (M+H)⁺.

Step 2:rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutan-1-ol

To a suspension of sodium hydride (60% dispersion in mineral oil, 20.31g, 508.0 mmol) in THF (1200 mL) at 0° C. under a N₂ atmosphere was addeda solution of meso-2,3-dimethylbutane-1,4-diol (40.0 g, 338.0 mmol) inTHF (200 mL) dropwise over 20 min. After addition, the reaction washeated at 55° C. for 45 min and cooled to 0° C. The reaction mixture wastreated with a solution of tert-butyldimethylsilyl chloride (51.0 g,338.0 mmol) in THF (200 mL). The reaction was stirred at roomtemperature for 12 h. The reaction was quenched by adding saturatedNH₄Cl (500 mL) and diluted with EtOAc (500 mL). The separated aqueouslayer was extracted with EtOAc (3×500 mL) and the combined organicextracts was washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure to giverac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutan-1-ol(70.0 g, 301.0 mmol, 89% yield) which was used as such in next step. MS(ESI, +ve ion) m/z 233.0 (M+H)⁺.

Step 3: rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanal

To a solution ofrac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutan-1-ol(70.0 g, 301.0 mmol) and (diacetoxyiodo)benzene (107.0 g, 301.0 mmol) inDCM (250 mL) was added 2,2,6,6-tetramethyl-1-piperidinyloxy (2.35 g,15.06 mmol) in one portion at room temperature. The reaction mixture wasstirred for 12 h at room temperature. The reaction mixture was pouredinto DCM (500 mL) and washed with saturated aqueous sodium bicarbonatesolution (250 mL) and brine (250 mL). The organic layer was dried overMgSO₄, and concentrated under reduced pressure. The crude material waspurified by column chromatography using silica gel 60-120 mesh, elutingwith 0% to 10% EtOAc in hexane to giverac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanal (45.0g, 195.0 mmol, 64.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 3.51 (dd,J=10.1, 5.2 Hz, 1H), 3.40 (dd, J=10.0, 8.2 Hz, 1H), 2.35-2.22 (m, 2H),0.94 (d, J=6.8 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H), 0.83 (s, 9H). 0.03 (s,3H) 0.01 (s, 3H). MS (ESI, +ve) m/z 231.2 (M+H)⁺.

Step 4: rac-(2S,3S)-2,3-dimethylpent-4-en-1-ol

A solution of methyl triphenylphosphonium bromide (185.0 g, 521.0 mmol)in THF (1500 mL) was treated with n-butyllithium (2.5 M solution inhexane, 174.0 mL, 18.8 mmol) at 0° C. After 10 min, the resulting yellowmixture was allowed to stir at room temperature for 20 min. A solutionof rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanal(40.0 g, 174.0 mmol) in THF (50 mL) was added to the reaction mixture at−78° C. After 10 min, the reaction mixture was allowed to stirred at 0°C. for 2 h and then quenched with saturated aqueous NH₄Cl (500 mL)solution and water (200 mL). Diethylether (500 mL) was added and layerswere separated. The aqueous layer was extracted with ether (3×500 mL).The combined organic layer was dried over MgSO₄, and concentrated underreduced pressure to get the crude material. The crude compound wasdissolved in DCM (300 mL) and treated with 1.0 N HCl in diethylether(250 mL). The reaction mixture was stirred at room temperature for 30min. The reaction mixture was concentrated under reduced pressure andthe crude product was purified by column chromatography using silica gel(60-120 mesh), eluting with 0% to 30% EtOAc in hexane to giverac-(2S,3S)-2,3-dimethylpent-4-en-1-ol (8.0 g, 70.1 mmol, 40.2% yield).¹H NMR (300 MHz, DMSO-d₆) δ 5.82-5.61 (m, 1H), 5.04-4.87 (m, 2H), 4.37(t, J=5.2 Hz, 1H), 3.39-3.25 (m, 1H), 3.19 (ddd, J=10.5, 6.7, 5.2 Hz,1H), 2.33-2.16 (m, 1H), 1.56-1.36 (m, 1H), 0.95 (d, J=6.9 Hz, 3H), 0.76(d, J=6.9 Hz, 3H). MS (ESI, +ve) m/z 115.1 (M+H)⁺.

Step 5: rac-(2S,3S)-2,3-dimethylpent-4-en-1-yl methanesulfonate

To a solution of rac-(2S,3S)-2,3-dimethylpent-4-en-1-ol (5.0 g, 43.8mmol) and triethylamine (13.43 mL, 96.0 mmol) in DCM (200 mL) was addedmethanesulfonyl chloride (5.12 mL, 65.7 mmol, 1.5 equiv) at 0° C. Thereaction mixture was stirred at 0° C. for 1 h. Then the reaction wasquenched with saturated NH₄Cl (100 mL) solution and extracted with EtOAc(3×200 mL) and the combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure togive rac-(2S,3S)-2,3-dimethylpent-4-en-1-yl methanesulfonate which wasused without further purification. MS (ESI, +ve) m/z 193.2 (M+H)⁺.

Step 6: rac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)thio)pyrimidine

A solution of 2-mercapto-pyrimidine (27.5 g, 245.0 mmol) and potassiumcarbonate (36.3 g, 263.0 mmol) in DMF (1000 mL) was stirred at roomtemperature for 10 min. A solution ofrac-(2S,3S)-2,3-dimethylpent-4-en-1-yl methanesulfonate (337 g, 175.0mmol) in THF (1000 mL) was added at room temperature. The resultingmixture was heated to 50° C. for 4 h and stirred at room temperature for12 h. The crude mixture was quenched with cold water (500 mL) andextracted with EtOAc (3×500 mL). The combined organic layer wasconcentrated under reduced pressure. The crude material was purified bycolumn chromatography (EtOAc/hexanes, 0% to 15%, silica gel) to giverac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)thio)pyrimidine (19.0 g, 91.0mmol, 52% yield). ¹H NMR (300 MHz, Chloroform-d) δ 8.50 (d, J=4.7 Hz,2H), 6.94 (t, J=4.8 Hz, 1H), 5.76 (ddd, J=16.8, 10.6, 8.2 Hz, 1H),5.19-4.97 (m, 2H), 3.25 (dd, J=13.2, 5.9 Hz, 1H), 2.99 (dd, J=13.1, 7.9Hz, 1H), 2.50-2.32 (m, 1H), 1.93-1.74 (m, 1H), 1.07 (d, J=6.8 Hz, 3H),1.00 (d, J=6.9 Hz, 3H). MS (ESI, +ve) m/z 209.0 (M+H)⁺.

Step 7: rac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)sulfonyl)pyrimidine

To a solution ofrac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)thio)pyrimidine (25.0 g,120.0 mmol) in acetonitrile (500 mL) and water (50 mL) was added sodiumtungstate dehydrate (7.92 g, 24.0 mmol) followed by hydrogen peroxide(61.3 mL, 600.0 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was quenched with saturatedsodium thiosulfate (750 mL). The reaction mixture was extracted withethyl-acetate (3×1000 mL) and combined organic layer was dried oversodium-sulphate, filtered and concentrated under reduced pressure togive rac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)sulfonyl)pyrimidine(25.0 g, 104.0 mmol, 86% yield). ¹H NMR (400 MHz, Chloroform-d) δ 8.98(d, J=4.8 Hz, 2H), 7.59 (t, J=4.9 Hz, 1H), 5.78-5.59 (m, 1H), 5.14-5.01(m, 2H), 3.58 (dd, J=14.3, 4.0 Hz, 1H), 3.32 (dd, J=14.3, 8.5 Hz, 1H),2.48-2.28 (m, 2H), 1.10 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H). MS(ESI, +ve) m/z 241.2 (M+H)⁺.

Step 8: rac-(2S,3S)-2,3-dimethylpent-4-ene-1-sulfonamide

To a solution ofrac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)sulfonyl)pyrimidine (25.0 g,104.0 mmol) in methanol (500 mL) was added sodium methoxide (22.48 g,104.0 mmol). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was concentrated under reduced pressure. Thecrude mixture was diluted with water (500 mL) and washed with ethylacetate (3×250 mL). Sodium acetate (10.24 g, 125 mmol) andhydroxylamine-o-sulfonic acid (14.12 g, 125 mmol) was added to theaqueous layer. The reaction mixture was stirred at room temperature for12 h. The reaction mixture was extracted with MTBE (3×500 mL) and thecombined organic layer was washed with saturated sodium carbonate (2×300mL), dried over sodium-sulphate, filtered and concentrated under reducedpressure to give rac-(2S,3S)-2,3-dimethylpent-4-ene-1-sulfonamide (14.0g, 79.0 mmol, 76% yield). ¹H NMR (400 MHz, Chloroform-d) δ 5.71 (ddd,J=17.8, 10.5, 7.2 Hz, 1H), 5.19-4.92 (m, 4H), 3.19 (dd, J=14.6, 3.7 Hz,1H), 2.89 (dd, J=14.6, 8.3 Hz, 1H), 2.36 (q, J=6.2 Hz, 1H), 2.19 (th,J=7.5, 4.0, 3.3 Hz, 1H), 1.11 (dd, J=6.6, 2.9 Hz, 3H), 1.03 (dd, J=6.7,2.9 Hz, 3H). MS (ESI, +ve) m/z 178.2 (M+H)⁺.

(S)-Hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

Step 1: (S)-tert-butyl4-benzyl-2-(hydroxymethyl)piperazine-1-carboxylate

To a solution of (S)-1-boc-2-(hydroxymethyl)piperazine (5.0 g, 23.12mmol) in 1,2-dichloroethane (100 mL) was added benzaldehyde (7.04 mL,69.4 mmol). The resulting mixture was then stirred at room temperaturefor 30 min, and then sodium triacetoxyborohydride (6.85 mL, 46.2 mmol)was added. The resulting mixture was then stirred at room temperatureovernight. Then, the mixture was quenched with saturated NaHCO₃(20 mL)and was stirred at room temperature for 10 min. The organic layer wascollected and aqueous layer was extracted with EtOAc (1×30 mL). Thecombined organic extracts were then dried over MgSO₄ and concentrated invacuo. Chromatographic purification of the residue (silica gel, 0% to100% EtOAc/heptane) provided (S)-tert-butyl4-benzyl-2-(hydroxymethyl)piperazine-1-carboxylate (5.86 g, 19.13 mmol,83% yield) as an oil. MS (ESI, +ve ion) m/z 307.3 (M+H)⁺.

Step 2: (S)-(4-benzylpiperazin-2-yl)methanol

To a solution of (S)-tert-butyl4-benzyl-2-(hydroxymethyl)piperazine-1-carboxylate (5.86 g, 19.13 mmol)in DCM (30 mL) was added trifluoroacetic acid (11.37 mL, 153 mmol).After addition, the mixture was then stirred at room temperature for 2.5h. Then, additional trifluoroacetic acid (7 mL) was added and themixture was stirred at room temperature for an additional 1 h. Then, themixture was concentrated in vacuo and H₂O (10 mL) was added. The mixturewas then adjusted to pH=14 with NaOH (1 N). The mixture was thenextracted with EtOAc (3×30 mL). The combined organic extracts were driedover MgSO₄, concentrated, and dried in vacuo at 40° C. overnightprovided (S)-(4-benzylpiperazin-2-yl)methanol as an oil that was usedwithout further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.26-7.38(5H, m) 3.62-3.81 (2H, m) 3.54 (2H, d, J=4.11 Hz) 3.25-3.35 (2H, m)3.02-3.14 (1H, m) 2.77-2.90 (2H, m) 2.41 (1H, td, J=11.88, 2.45 Hz)2.18-2.30 (1H, m). MS (ESI, +ve ion) m/z 207.1 (M+H)⁺.

Step 3:(S)-1-(4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloroethanone

To a solution of (S)-(4-benzylpiperazin-2-yl)methanol (1.4 g, 6.79 mmol)and triethylamine (2.83 mL, 20.36 mmol) in DCM (5 mL) at 0° C. under N₂was added chloroacetyl chloride (0.540 mL, 6.79 mmol) dropwise. Afteraddition, the mixture was then stirred at 0° C. for 48 min. Then, MeOH(10 mL) was added and the mixture was concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0% to 100%EtOAc/heptane) provided(S)-1-(4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloroethanone (530mg, 1.874 mmol, 27.6% yield) as an oil. MS (ESI, +ve ion) m/z 283.1(M+H)⁺.

Step 4: (S)-8-benzylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of(S)-1-(4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloroethanone (530mg, 1.874 mmol) in THF (40 mL) at 0° C. under N₂ was added potassiumtert-butoxide (421 mg, 3.75 mmol). After addition, the mixture wasstirred at 0° C. for 2 h. LCMS showed no starting material. Then, MeOH(10 mL) was added and the mixture was concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0% to 100%EtOAc/heptane) provided(S)-8-benzylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (262 mg, 1.064mmol, 56.8% yield) as an oil. MS (ESI, +ve ion) m/z 247.1 (M+H)⁺.

Step 4: (S)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

A solution of (S)-8-benzylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one(262 mg, 1.064 mmol) and acetic acid (0.123 mL, 2.127 mmol) in methanol(2.5 mL) in a pressure vial was added a solution of palladium (5% onactivated carbon, 34 mg, 0.319 mmol) in EtOAc (0.3 mL). Then, themixture was degassed with hydrogen 5 times, and then was charged withhydrogen at 40 psi. The mixture was then stirred for 3.5 h. LCMS showedsome starting material. Then, palladium (5% on activated wood carbon, 34mg, 0.319 mmol) and acetic acid (0.123 mL, 2.127 mmol) were added. Then,the mixture was degassed 5 times with hydrogen, and then charged withhydrogen at 40 psi. The resulting mixture was stirred at roomtemperature overnight at 40 psi. Then, the mixture was filtered throughcelite and the celite was washed with MeOH/EtOAc 1:1 (2×3 mL). Thecombined filtrates were concentrated and dried in vacuo provided(S)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (166 mg, 1.063 mmol,100% yield) as an oil, which was used without further purification. MS(ESI, +ve ion) m/z 157.1 (M+H)⁺.

(3S,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one AND(3R,9aS)-3-methylhexahydropyraxion[2,1-c][1,4]oxazin-4(3H)-one

Step 1:(S)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-oneand(R)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one

To a solution of (S)-(4-benzylpiperazin-2-yl)methanol (1.4 g, 6.79 mmol)and triethylamine (2.83 mL, 20.36 mmol) in DCM (10 mL) at 0° C. wasadded 2-chloropropionyl chloride (0.862 mL, 6.79 mmol). After addition,the mixture was stirred at 0° C. for 2 h. LCMS showed no startingmaterial. Then, MeOH (10 mL) was added and the mixture was concentratedin vacuo. Chromatographic purification of the residue (silica gel, 0% to100% EtOAc/heptane) provided(S)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one(176 mg, 0.593 mmol, 8.74% yield) as an oil and the first eluting isomerfrom the silica gel column. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.28-7.40(5H, m) 4.46-4.73 (2H, m) 4.14 (1H, br s) 3.69-4.03 (3H, m) 3.41-3.63(2H, m) 3.10 (1H, br s) 2.93 (1H, br s) 2.35 (1H, br s) 2.02-2.23 (1H,m) 1.65-1.69 (3H, m). MS (ESI, +ve ion) m/z 297.0 (M+H)⁺. In addition,(R)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one(142 mg, 0.478 mmol, 7.1% yield) was isolated as an oil and the secondeluting isomer from the silica gel column. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.27-7.40 (5H, m), 4.60-4.72 (1H, m), 4.44-4.59 (1H, m),3.97 (1H, d, J=4.30 Hz), 3.68-3.93 (3H, m), 3.51 (2H, d, J=18.58 Hz),3.07 (1H, br s), 2.92 (1H, br s), 2.11-2.45 (2H, m), 1.64-1.73 (3H, m).MS (ESI, +ve ion) m/z 297.0 (M+H)⁺.

Step 2:(3S,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of(R)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one(142 mg, 0.478 mmol) in THF (50 mL) under nitrogen at 0° C. was addedpotassium tert-butoxide (59.1 mg, 0.526 mmol). The resulting mixture wasthen stirred at 0° C. for 1 h and at room temperature for 10 d. Then,MeOH (10 mL) was added and the mixture was concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0% to 100%EtOAc/heptane) provided(3S,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one(33 mg, 0.127 mmol, 26.5% yield) as an oil. ¹H NMR (400 MHz,DICHLOROMETHANE-d₂) δ 7.11-7.28 (6H, m), 4.31-4.42 (1H, m), 4.02-4.10(1H, m), 3.69-3.77 (1H, m), 3.54-3.63 (1H, m), 3.37-3.49 (3H, m),2.63-2.80 (3H, m), 1.92-2.05 (2H, m), 1.31 (3H, d, J=6.85 Hz). MS (ESI,+ve ion) m/z 261.1 (M+H)⁺.

Step 3: (3 S,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of(3S,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one(33 mg, 0.127 mmol) in methanol (0.5 mL) was added acetic acid (0.015mL, 0.254 mmol) and palladium (10 wt % dry basis on activated carbon,wet, degussa type, 6.74 mg, 0.063 mmol). The resulting mixture was thenpurged with hydrogen, then was charged with hydrogen at 40 psi. Theresulting mixture was then stirred at room temperature overnight. Then,the mixture was filtered through celite and the celite was washed withEtOAc (2×3 mL). The combined filtrates were concentrated in vacuo andchromatographic purification of the residue (silica gel, 0% to 50%MeOH/DCM) provided (3S,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (20 mg,0.118 mmol, 93% yield) as an oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ4.43-4.58 (1H, m), 4.09-4.19 (1H, m), 3.86 (1H, dd, J=12.52, 4.50 Hz),3.66-3.75 (1H, m), 3.53 (1H, td, J=7.53, 3.72 Hz), 2.97-3.12 (2H, m),2.65-2.87 (3H, m), 1.41 (3H, d, J=6.85 Hz). MS (ESI, +ve ion) m/z 171.1(M+H)⁺.

Step 4:(3R,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of(S)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one(176 mg, 0.593 mmol) in THF (50 mL) at 0° C. under nitrogen was addedpotassium tert-butoxide (100 mg, 0.890 mmol). After addition, themixture was then stirred at 0° C. for 30 min. LCMS showed no startingmaterial. Then, saturated NaHCO₃(5 mL) was added and the mixture wasextracted with EtOAc (2×20 mL). The combined organic extracts were driedover MgSO₄, concentrated, and dried in vacuo provided(3R,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one(154 mg, 0.592 mmol, 100% yield) as an oil, which was used withoutpurification. MS (ESI, +ve ion) m/z 261.0 (M+H)⁺.

Step 5: (3R,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of(3R,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one(154 mg, 0.592 mmol) in methanol (2 mL) was added a solution ofpalladium (10 wt % dry basis on activated carbon, wet, degussa type,18.89 mg, 0.177 mmol) in EtOAc (0.2 mL). The resulting mixture was thenpurged with hydrogen five times and charged with hydrogen at 40 psi. Theresulting mixture was then stirred for 10 d. Then, the mixture wasfiltered through celite and the celite was washed with EtOAc (2×5 mL).The combined filtrates were concentrated. Chromatographic purificationof the residue (silica gel, 0% to 20% MeOH/DCM) provided(3R,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (93 mg,0.546 mmol, 92% yield) as an oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δppm 4.27-4.45 (1H, m), 4.05 (1H, q, J=6.85 Hz), 3.74 (1H, dd, J=12.23,4.60 Hz), 3.54-3.63 (1H, m), 3.24-3.36 (1H, m), 2.84-2.91 (1H, m), 2.80(1H, dd, J=11.74, 2.74 Hz), 2.50-2.67 (3H, m), 1.32 (3H, d, J=6.85 Hz).MS (ESI, +ve ion) m/z 171.1 (M+H)⁺.

(3S,9aS)-3-Methyloctahydropyrazino[2,1-c][1,4]oxazine

To a solution of(3S,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (52 mg,0.306 mmol) in 1,4-dioxane (4 mL) at room temperature under nitrogen wasadded lithium aluminium hydride (2.0 M in THF, 1.22 mL, 2.44 mmol)dropwise. After addition, the mixture was then stirred at 80° C. for 6h. Then, the mixture was quenched with 2-propanol (1 mL) at 0° C.followed by saturated Na₂SO₄ (3 mL). The mixture was then stirred atroom temperature for 30 min and then was filtered. The filtered cake waswashed with MeOH (2×5 mL). The combined filtrates were concentrated anddried in vacuo. The residue was then dissolved in MeOH (5 mL) and silicagel was added. The mixture was concentrated and dried in vacuo. Thesolid mixture was then purified by silica gel column chromatographyusing ISCO instrument (solid loading, 0% to 20% ammonia in MeOH 2 M/DCM)provided (3S,9aS)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine (67 mg,0.429 mmol, 140% yield) as a solid that contained residual solvent andwas used without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ3.94 (1H, dt, J=6.55, 3.37 Hz), 3.72 (1H, q, J=7.04 Hz), 3.52-3.59 (2H,m), 3.03-3.10 (2H, m), 2.86-2.96 (1H, m), 2.68-2.82 (5H, m), 1.90 (1H,br s), 1.34 (3H, d, J=6.65 Hz). MS (ESI, +ve ion) m/z 157.1 (M+H)⁺.

(3R,9aS)-3-Methyloctahyldropyrazino[2,1-c][1,4]oxazine

To a solution of(3R,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (80 mg,0.470 mmol) in 1,4-dioxane (5 mL) under N₂ at room temperature was addedlithium aluminium hydride (1.0 M in THF, 1.88 mL, 1.88 mmol) dropwise.After addition, the mixture was stirred at 80° C. for 6 h. Then, themixture was quenched 2-propanol (1 mL) at 0° C. followed by saturatedNa₂SO₄ (3 mL). The mixture was then stirred at room temperature for 30min and then was filtered. The filtered cake was washed with MeOH (2×5mL). The combined filtrates were concentrated and dried in vacuo. Theresidue was then dissolved in MeOH (5 mL) and silica gel was added. Themixture was concentrated and dried in vacuo. The solid mixture was thenpurified by silica gel column chromatography using ISCO instrument(solid loading, 0% to 20% ammonia in MeOH 2 M/DCM) provided(3R,9aS)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine (20 mg, 0.128mmol, 27.2% yield) as an oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ3.92 (1H, ddd, J=6.50, 3.96, 2.25 Hz), 3.42-3.50 (1H, m), 3.30-3.37 (1H,m), 2.79-2.92 (2H, m), 2.53-2.68 (2H, m), 2.37-2.50 (3H, m), 2.06-2.24(2H, m), 1.90 (1H, br s), 1.33 (3H, d, J=6.65 Hz). MS (ESI, +ve ion) m/z157.2 (M+H)⁺.

(R)-Hexahydro-1H-pyrido[1,2-a]pyrazin-4(6H)-one

Step 1: (R)-tert-butyl2-((((benzyloxy)carbonyl)amino)methyl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl 2-(aminomethyl)piperidine-1-carboxylate(475 mg, 2.216 mmol) in DCM (5.0 mL) at 0° C. was added iPr₂Net (0.424mL, 2.438 mmol) followed by benzyl chloroformate (0.693 mL, 2.438 mmol).The resulting mixture was then stirred at 0° C. for 2 h and at roomtemperature for 14 h. Then, saturated NaHCO₃(30 mL) was added to themixture and the mixture was stirred at room temperature for 3 min. Theorganic layer was collected and aqueous layer was extracted with EtOAc(1×20 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated in vacuo. Chromatographic purification of the residue(silica gel, 0% to 100% EtOAc/heptane) provided (R)-tert-butyl2-((((benzyloxy)carbonyl)amino)methyl)piperidine-1-carboxylate (772 mg,2.216 mmol, 100% yield) as an oil. MS (ESI, +ve ion) m/z 371.1 (M+Na)⁺.

Step 2: (R)-benzyl (piperidin-2-ylmethyl)carbamate

A solution of (R)-tert-butyl2-((((benzyloxy)carbonyl)amino)methyl)piperidine-1-carboxylate (772 mg,2.216 mmol) in DCM (5 mL) was added trifluoroacetic acid (1.646 mL,22.16 mmol). The resulting mixture was then stirred at room temperaturefor 2 h. Then, iPr₂Net (3.85 mL, 22.16 mmol) was added dropwise to themixture at 0° C. and the mixture was stirred at room temperature for 5min. Then, the mixture was concentrated in vacuo and chromatographicpurification of the residue (silica gel, 0% to 100% EtOH:EtOAc(3:1)/heptane) provided (R)-benzyl (piperidin-2-ylmethyl)carbamate (495mg, 90% yield) as an oil. MS (ESI, +ve ion) m/z 249.2 (M+H)⁺.

Step 3: (R)-benzyl ((1-(2-chloroacetyl)piperidin-2-yl)methyl)carbamate

To a solution of (R)-benzyl (piperidin-2-ylmethyl)carbamate (150 mg,0.604 mmol) in 1,2-dichloroethane (1 mL) and DCM (1 mL) at 0° C. undernitrogen was added iPr₂Net (0.168 mL, 0.966 mmol) followed bychloroacetyl chloride (0.063 mL, 0.785 mmol). After addition, themixture was then stirred at 0° C. for 1 h. Then, the mixture wasquenched with saturated NaHCO₃(2.5 mE) and extracted with EtOAc (2×3mL). The combined organic extracts were then dried over Na₂SO₄ andconcentrated in vacuo. Chromatographic purification of the residue(silica gel, 0% to 100% EtOAc/heptane) provided (R)-benzyl((1-(2-chloroacetyl)piperidin-2-yl)methyl)carbamate (126 mg, 0.388 mmol,64.2% yield) as a solid. MS (ESI, +ve ion) m/z 325.1 (M+H)⁺.

Step 4: (R)-benzyl4-oxohexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate

To a solution of (R)-benzyl((1-(2-chloroacetyl)piperidin-2-yl)methyl)carbamate (126 mg, 0.388 mmol)in tetrahydrofuran (5 mL) was added sodium hydride (60% dispersion inmineral oil, 31 mg, 0.776 mmol) in portions. After addition, the mixturewas then stirred at room temperature for 5 h. Then, the mixture wascarefully quenched with water (5 mL). The mixture was then extractedwith EtOAc (2×10 mL). The combined organic extracts were then dried overNa₂SO₄ and concentrated in vacuo. Chromatographic purification of theresidue (silica gel, 0% to 100% EtOAc/heptane) provided (R)-benzyl4-oxohexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate (112 mg, 0.388mmol, 100% yield) as an oil. MS (ESI, +ve ion) m/z 289.1 (M+H)⁺.

Step 5: (R)-hexahydro-1H-pyrido[1,2-a]pyrazin-4(6H)-one

To a solution of (R)-benzyl4-oxohexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate (112 mg, 0.388mmol) in ethanol (3 mL) was added ammonium formate (122 mg, 1.942 mmol)and 10% palladium on carbon (124 mg, 0.117 mmol). The resulting mixturewas then stirred at 70° C. for 1 h. The mixture was filtered throughcelite and the filter cake was washed with a mixture of EtOAc and MeOH(1:1, 3×2 mL). The combined filtrates were concentrated andchromatographic purification of the residue (silica gel, 0% to 15% 2 Mammonia in MeOH/DCM) provided(R)-hexahydro-1H-pyrido[1,2-a]pyrazin-4(6H)-one (54 mg, 0.350 mmol, 90%yield) as an oil. MS (ESI, +ve ion) m/z 155.1 (M+H)⁺.

1-(Dihydro-1H-pyrazino[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)ethanone

Step 1: tert-butyl8-acetylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate

To stirred solution of tert-butylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.680 g, 2.82mmol) in DCM (10 mL) was added at room temperature under argondiisopropylethylamine (1.078 mL, 6.20 mmol) followed by2,5-dioxopyrrolidin-1-yl acetate (0.885 g, 5.64 mmol) in one portion asa solid. The resulting mixture was stirred at room temperature for 24 h.The crude mixture was directly loaded onto a silica gel precolumn (25g), previously covered with a layer of sodium bicarbonate, and subjectedto flash column chromatography on a 24 g ISCO gold column eluting with0% to 3% MeOH/DCM to give tert-butyl8-acetylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate as anoil. This was taken onto the next step without further purification. MS(ESI, +ve ion) m/z 306.4 (M+Na)⁺.

Step 2:1-(dihydro-1H-pyrazino[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)ethanone

To a solution of tert-butyl8-acetylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate in DCM(10 mL) was added 2,2,2-trifluoroacetic acid (2.0 mL) at roomtemperature. The resulting mixture was stirred at room temperatureovernight and the volatiles were removed to give1-(hexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)ethanone2,2,2-trifluoroacetate as a solid which was used without furtherpurification.

Step 1: tert-butyl8-(methylsulfonyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate

To a stirred ice-cooled mixture of tert-butylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (1.000 g, 4.14mmol) and diisopropylethylamine (1.442 mL, 8.29 mmol) in DCM (14 mL) wasdropwise added methanesulfonyl chloride (0.385 mL, 4.97 mmol) via asyringe. The resulting mixture was stirred at 0° C. for 10 min andstirred at ambient temperature for 19 h. The volatiles were removed andthe residue was loaded onto a silica gel precolumn (25 g) and subjectedto combi-flash column chromatography on a 24 g ISCO gold column elutingwith 0% to 100% MeOH/DCM to give tert-butyl8-(methylsulfonyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate(1.30 g, 4.07 mmol, 98% yield) as an oil. MS (ESI, +ve ion) m/z 320.1(M+1)⁺.

Step 2: 2-(methylsulfonyl)octahydro-1H-pyrazino[1,2-a]pyrazine

To a stirred solution of tert-butyl8-(methylsulfonyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate(1.30 g, 4.07 mmol) in DCM (20 mL) was added 2,2,2-trifluoroacetic acid(2.0 mL, 4.14 mmol) via a syringe. The resulting mixture was stirred atroom temperature for 2.5 h. Additional TFA (2×2.5 mL) was added over thefirst 2 h. The volatiles were removed in vacuo and the residue wassubjected to high vacuum overnight to give 2.4 g of2-(methylsulfonyl)octahydro-1H-pyrazino[1,2-a]pyrazine2,2,2-trifluoroacetate as a solid which was used without furtherpurification. MS (ESI, +ve ion) m/z 220.2 (M+1)⁺.

Step 1: tert-butyl8-(3-(phenylsulfonyl)propanoyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate

To a stirred mixture of tert-butylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.46 g, 1.906mmol) and 3-(phenylsulfonyl)propionic acid (0.490 g, 2.287 mmol) in DCM(6.5 mL) was added at room temperature iPr₂Net (0.829 mL, 4.77 mmol) viaa syringe followed by HATU (1.450 g, 3.81 mmol) in one portion as asolid. The resulting mixture was stirred at room temperature for 75 min.The crude mixture was directly loaded onto a silica gel precolumn (25 g)and subjected to combi-flash column chromatography on a 24-g ISCO goldcolumn eluting with 0% to 15% MeOH/DCM to give 1.28 g tert-butyl8-(3-(phenylsulfonyl)propanoyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylateas an oil which was taken onto the next step without furtherpurification. MS (ESI, +ve ion) m/z 438.2 (M+1)⁺.

Step 2: 1-(dihydro-1H-pyrazino[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)-3-(phenylsulfonyl)propan-1-one

A mixture of tert-butyl8-(3-(phenylsulfonyl)propanoyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate(1.28 g, 2.93 mmol) and 2,2,2-trifluoroacetic acid (4.0 mL, 2.93 mmol)in DCM (15 mL) was stirred at room temperature for 50 min. The volatileswere removed and the residue was subjected to high vacuum overnight togive 1.5 g of1-(dihydro-1H-pyrazino[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)-3-(phenylsulfonyl)propan-1-oneas an oil that was used without further purification. MS (ESI, +ve ion)m/z 338.1 (M+1)⁺.

Step 1: tert-butyl8-isopropylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate

A mixture of tert-butylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.53 g, 2.196mmol) and acetone (0.806 mL, 10.98 mmol) in DCM (5.0 mL) was stirred atrt for 10 min before sodium triacetoxyhydroborate (2.327 g, 10.98 mmol)was added at room temperature in one portion as a solid. The resultingmixture was stirred at room temperature for 24 h. The reaction wasquenched with MeOH (5 mL) and the resulting slurry was directly loadedonto a silica gel precolumn (25 g) and subjected to combi-flash columnchromatography on a 12 g ISCO gold column eluting with 0% to 20%MeOH/DCM to give tert-butyl8-isopropylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.65g, 2.293 mmol, 104% yield) as an oil. MS (ESI, +ve ion) m/z 284.3(M+1)⁺.

Step 2: 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine

A mixture of tert-butyl8-isopropylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.65g, 2.293 mmol) and 2,2,2-trifluoroacetic acid (4.0 mL, 2.293 mmol) inDCM (15 mL) was stirred at room temperature for 2 h. The volatiles wereremoved in vacuo and the residue was subjected to high vacuum overnightto give 1.74 g of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine as anoil that was used without further purification. MS (ESI, +ve ion) m/z184.2 (M+1)⁺.

The title compound was synthesized, from (1R,4R)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (AstaTech, Inc.), similarlyusing the protocol in the synthesis of2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z141.2 (M+1)⁺.

The title compound was synthesized, from (1S,4S)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (AstaTech, Inc.), similarlyusing the protocol in the synthesis of2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z141.2 (M+1)⁺.

The title compound was synthesized, from cis-tert-butyl3,5-dimethylpiperazine-1-carboxylate (AK Scientific), similarly usingthe protocol in the synthesis of2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z173.2 (M+1)⁺.

The title compounds were synthesized and used as a mixture, fromcis-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (AK Scientific),similarly using the protocol in the synthesis of2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z157.1 and 115.3 (M+1)⁺.

The title compound was synthesized, from (S)-tert-butyl3-methylpiperazine-1-carboxylate, similarly using the protocol in thesynthesis of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI,+ve ion) m/z 143.2 (M+1)⁺.

The title compound was synthesized, from 1,4-dioxepan-6-one (Enamine),similarly using the protocol in the synthesis of2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z187.2 (M+1)⁺.

The title compound was synthesized, from (3S,5S)-tert-butyl3,5-dimethylpiperazine-1-carboxylate (Anichem), similarly using theprotocol in the synthesis of2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z157.2 (M+1)⁺.

The title compound was synthesized, from piperazin-2-one (AKScientific), similarly using the protocol in the synthesis (Step 1) of2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine.

The title compound was synthesized, from tert-butylpiperazine-1-carboxylate, similarly using the protocol in the synthesisof 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion)m/z 157.1 (M+1)⁺.

To a stirred solution of 5,6-dihydro-2h-pyran-2-one (0.228 mL, 2.65mmol) in DCM (1.0 mL) was added under argon a solution ofpiperazine-1-carboxylic acid tert-butyl ester (469 mg, 2.52 mmol) in DCM(2.0 mL). The resulting mixture was stirred at room temperature for aperiod of 3 d before trifluoroacetic acid (2.5 mL, 33.7 mmol) was addeddropwise via a syringe. The resulting mixture was stirred at roomtemperature for a period of 2 h. The mixture was concentrated in vacuoand the residue was dried to give impure4-(piperazin-1-yl)tetrahydro-2H-pyran-2-one. This was used withoutfurther purification. MS (ESI, +ve ion) m/z 185.1 (M+1)⁺.

Step 1: 2-benzyl-8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine and2-benzyl-8-fluoro-2,3,4,6,7,9a-hexahydro-1H-pyrido[1,2-a]pyrazine and2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine

To a stirred solution of2-benzylhexahydro-1H-pyrido[1,2-a]pyrazin-8(2H)-one (200 mg, 0.819 mmol,AstaTech) in DCM (5.0 mL) cooled in brine-ice bath was addedbis(2-methoxyethyl)aminosulfur trifluoride solution (50% in THF, 0.989mL, 2.456 mmol) dropwise via a syringe. The resulting mixture wasstirred for 2 h at −5° C. and 3 h at ambient temperature. The crudemixture was directly loaded onto a silica gel precolumn (25 g) andsubjected to flash column chromatography on a 12 g ISCO gold columneluting with 0% to 10% MeOH/DCM to give 170 mg of a mixture of2-benzyl-8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine,2-benzyl-8-fluoro-2,3,4,6,7,9a-hexahydro-1H-pyrido[1,2-a]pyrazine, and2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine. Themixture was directly used in the next step. MS (ESI, +ve ion) m/z 267.2and 247.2 (M+1)⁺.

Step 2: 8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine and8-fluorooctahydro-1H-pyrido[1,2-a]pyrazine

A mixture of 2-benzyl-8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine,2-benzyl-8-fluoro-2,3,4,6,7,9a-hexahydro-1H-pyrido[1,2-a]pyrazine and2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine (250mg, 0.939 mmol) and palladium (5 wt % dry basis on activated carbon,wet, degussa type, spatula tip) in EtOH (25 mL) and concentratedhydrochloric acid (5 mL) was hydrogenated with hydrogen gas at 40-45 psifor a period of 22 h. The reaction was quenched with water (5 mL) andthe mixture was filtered through a layer of celite covered with sand.The filtrate was concentrated in vacuo to give8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine AND8-fluorooctahydro-1H-pyrido[1,2-a]pyrazine as a colorless film which wasused without further purification. MS (ESI, +ve ion) m/z 177.2 and 159.2(M+1)⁺.

Step 1: tert-butyl 4-(3-acetyl-4-hydroxyphenyl)piperazine-1-carboxylate

To a stirred ice-cooled mixture of 5′-bromo-2′-hydroxyacetophenone(2.000 g, 9.30 mmol, Oakwood), 1-boc-piperazine (2.77 g, 14.88 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.426 g, 0.465 mmol), and2-(dicyclohexylphosphino)-2′-(n,n-dimethylamino)biphenyl (0.183 g, 0.465mmol) in THF (20 mL) was added dropwise lithium bis(trimethylsilyl)amide(1.0 M in THF, 32.6 mL, 32.6 mmol). The resulting mixture was stirred atambient temperature for 10 min before it was placed in an oil bath whichwas at room temperature. The oil bath was then heated to 70° C. and thereaction mixture was stirred at this temperature for 1.5 h. The mixturewas cooled in an ice bath before carefully quenched with ice-coldsaturated ammonium chloride aqueous solution. The resulting mixture waspoured into a mixture of 1 N aqueous HCl and saturated ammonium chlorideaqueous solutions and extracted with 10% MeOH/DCM (2×). The combinedorganics were washed with saturated ammonium chloride aqueous solution,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was dissolved in DCM and loaded onto silica gel precolumn andsubjected to flash column chromatography on a 40 g ISCO gold columneluting with 0% to 4% MeOH/DCM to give 1.84 g tert-butyl4-(3-acetyl-4-hydroxyphenyl)piperazine-1-carboxylate that was directlyused in the next step. MS (ESI, +ve ion) m/z 321.2 (M+1)⁺.

Step 2: tert-butyl4-(3-acetyl-4-(trifluoromethylsulfonyloxy)phenyl)piperazine-1-carboxylate

To a stirred solution of impure tert-butyl4-(3-acetyl-4-hydroxyphenyl)piperazine-1-carboxylate (1.30 g, 4.06 mmol)and triethylamine (2.258 mL, 16.23 mmol) in DCM (15 mL) was addedN-phenyl bis-trifluoromethane sulfonimide (2.90 g, 8.12 mmol) in oneportion as a solid. The resulting mixture was stirred at ambienttemperature for 2.5 d. The crude mixture was directly loaded onto asilica gel precolumn (25 g) and subjected to flash column chromatographyon a 40 g ISCO gold column eluting with 10% to 40% EtOAc/Hexanes to givetert-butyl4-(3-acetyl-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperazine-1-carboxylate(1.4 g, 3.09 mmol, 76% yield). MS (ESI, +ve ion) m/z 475.1 (M+1)⁺.

Step 3: tert-butyl4-(3-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate

A 25-mL single-necked round bottom flash previously charged withtert-butyl4-(3-acetyl-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperazine-1-carboxylate(1.17 g, 2.59 mmol), bis(pinacolato)diboron (1.642 g, 6.46 mmol),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.189 g,0.259 mmol), and potassium acetate (0.888 g, 9.05 mmol) was subjected to3 cycles of evacuation and back-filling with nitrogen before 1,4-dioxane(12 mL) was added. The resulting mixture under argon was placed in anoil bath and heated to 50° C. and stirred under argon at thistemperature for a period of 20 h. The temperature was lowered to 45° C.and the mixture was stirred overnight at this temperature. The crudereaction mixture was run through a silica gel plug. The filtrate wasconcentrated in vacuo and the residue was dissolved in DCM and loadedonto silica gel precolumn (25 g) and subjected to flash columnchromatography on a 24 g ISCO gold column eluting with 0% to 40%EtOAc/hexanes to give tert-butyl4-(3-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(380 mg, 0.883 mmol, 34.1% yield) as a solid. MS (ESI, +ve ion) m/z431.3 (M+1)⁺.

Step 4:1-(5-(piperazin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone

tert-Butyl4-(3-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylatein DCM was treated with TFA for the removal the Boc group.1-(5-(piperazin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanonewas isolated after concentration and used without further purification.MS (ESI, +ve ion) m/z 331.2 (M+1)⁺.

(2S)—N,N-BIS(4-METHOXYBENZYL)-2-METHYLPENT-4-ENE-1-SULFONAMIDE AND(2R)—N,N-BIS(4-METHOXYBENZYL)-2-METHYL-4-PENTENE-1-SULFONAMIDE

The title compound was prepared from Intermediate EE12 andpent-4-en-2-yl 4-methylbenzenesulfonate following a similar proceduredescribed below.

(2R,3R)—N,N-BIS (4-METHOXYBENZYL)-3-METHYLHEX-5-ENE-2-SULFONAMIDE AND(2S,3R)—N,N-BIS(4-METHOXYBENZYL)-3-METHYLHEX-5-ENE-2-SULFONAMIDE

N,N-bis(4-methoxybenzyl)ethanesulfonamide (Intermediate EE13; 1030 mg,2.95 mmol) was azeotroped in toluene under vacuum for 2 h. Under argon,THF was added and the solution was cooled to −78° C. N-butyllithiumsolution (2.5 M in hexane, 1.533 mL, 3.83 mmol) was then added and themixture was stirred at −78° C. for 60 min. (S)-pent-4-en-2-yl4-methylbenzenesulfonate (prepared according to the procedure by Sigman,M. S. et al., J. Am. Chem. Soc., 2012, 134(28), 11408-11411; 1417 mg,5.90 mmol) was added as a solution in 3 mL. THF was then added. After 5min the mixture was allowed to warm to ambient temperature and stirredovernight under argon. The mixture was quenched with satd NH₄Cl andextracted with EtOAc, dried over MgSO₄, and concentrated. The crudematerial was injected into a SiO₂ gel cartridge and purified bychromatography through a 40 g ISCO column, eluting with 5% to 10% to 20%to 40% EtOAc in hexane, to provide a 2.3:1 mixture of the titlecompounds (420 mg, 1.00 mmol, 34.1% yield).

Intermediate AA11A(S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLICACID

Step 1: (R)-6-CHLORO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,2′-OXIRANE]AND(R)-6-CHLORO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,2′-OXIRANE]

A 2 L 4-necked-RBF was charged with6-chloro-3,4-dihydro-1(2H)-naphthalenone (123 g, 681 mmol),trimethylsulfonium iodide (143 g, 701 mmol), and DMSO (1100 mL). KOH (76g, 1362 mmol) (pellets) was added. The suspension was stirred at ambienttemperature for 2 days, after which time crude ¹H NMR showed noremaining starting material. The solution was poured into 800 g ofcrushed ice, rinsed with MTBE (200 mL), and an additional portion ofMTBE (700 mL) was added. The resulting mixture was stirred for 5 min andafter partition, the bottom aqueous layer was extracted with MTBE twice(500 mL, 300 mL), and combined with the main MTBE extract. The combinedorganic stream was washed with brine (2×600 mL) and 330 g of Al₂O₃(neutral) was added. The resulting suspension was stirred for 5 min at22° C., filtered, and washed with MTBE (400 mL). The filtrate wasconcentrated to give the product as a red viscous oil (125 g, 94%).

Step 2: (S)-6-CHLORO-1,2,3,4-TETRAHYDRONAPHTHALENE-1-CARBALDEHYDE AND(R)-6-CHLORO-1,2,3,4-TETRAHYDRONAPHTHALENE-1-CARBALDEHYDE

A 3 L 3-necked-RBF was charged with racemic6-chloro-3,4-dihydro-2H-spiro[naphthalene-1,2′-oxirane] (160 g, 822mmol) and THF (1760 mL). After the batch was cooled to −8° C. with a dryice/IPA bath, boron trifluoride diethyl etherate (5.07 mL, 41.1 mmol)was added over 3 min. An exotherm raised the batch temp to 10° C.instantly. The batch was stirred at −5 to 0° C. for 5 min, and LC/MSanalysis of a sample (quenched into cold NaHCO₃ solution) showedcomplete conversion. The reaction was quenched by the addition of sat.NaHCO₃ (300 mL) at −5° C. followed by MTBE (400 mL) and the mixture wastransferred to a separatory funnel and rinsed with MTBE (240 mL). Afterpartition, the aqueous layer was discarded along with some white solid(likely boric acid or borax). The organic layer was washed with brine(350 mL) and concentrated under reduced pressure to give a red oil. Thecrude material was used directly in Step 4.

Step 3: (6-CHLORO-1,2,3,4-TETRAHYDRONAPHTHALENE-1,1-DIYL)DIMETHANOL

Racemic 6-chloro-1,2,3,4-tetrahydro-1-naphthalenecarbaldehyde wascharged onto a 3 L 3-necked-RBF and rinsed with diethylene glycol (1000mL). Formaldehyde (37% solution in H₂O; 652 mL, 8757 mmol) was added andthe resulting biphasic emulsion was cooled to 5° C. with a dry ice/IPAbath. KOH (45% aqueous solution, 652 mL, 11.9 mol) was added over −30min, maintaining the temperature below 20° C. After complete addition,the batch (20° C.) was slowly heated to 45° C. (Caution: exothermicreaction) and aged for 1 h. HPLC showed complete conversion. Someviscous insoluble tar was formed, which was removed prior to aqueousworkup. To the batch was added brine (500 mL) and the mixture wasextracted with DCM until the product content in the aqueous phase wasless than 5%. The combined DCM extract was concentrated to 750 mL as ared oil, washed with H₂O (500 mL), and the product began to crystallizeout. Upon separation, the clear top aqueous layer was discarded and thebottom layer was stirred in ice/H₂O bath for 30 min, filtered, andwashed with DCM (˜100 mL) and H₂O (100 mL). The product was dried underdry air/vacuum to give a first crop (113 g, 498 mmol, 57% yield). TheDCM layer from the resulting mother liquor was separated andconcentrated to 200-300 g (KF=0.5%), seeded, and stirred in ice/H₂O bathfor 30 min. The product was filtered, washed with DCM (50 mL), and driedin dry air/vacuum to give a second crop (14.3 g, 63.1 mmol, 7% yield)for a combined total yield of6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl)dimethanol of 127 g(64%).

Step 4:(S)-(6-CHLORO-1-(HYDROXYMETHYL)-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHYL4-BROMOBENZOATE

To a solution of2,6-bis((R)-5,5-dibutyl-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine(R,R-Kang Catalyst) (1.57 g, 2.64 mmol) in dry DCM (450 mL), copper(II)chloride (0.355 g, 2.64 mmol) was added and the resulting green coloredsolution was stirred at rt for 1 h. This solution was added via cannulato a solution of(6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl)dimethanol (30 g,132.73 mmol) in dry DCM (800 mL). The resulting mixture was cooled to−78° C. and a light green colored precipitation was observed. A solutionof 4-bromobenzoyl chloride (34.77 g, 158.79 mmol) in DCM (500 mL) wasthen slowly added, followed by the dropwise addition ofN-ethyl-N-isopropylpropan-2-amine (20 g, 154 mmol). The resultingreaction mixture was stirred at −78° C. for 3 h, then it was quenchedwith pH 3 phosphate buffer (1 L) and warmed to ambient temperature withvigorous stirring. The mixture was then diluted with DCM (2 L) and thelayers were separated. The organic phase was washed with pH 3 buffer (1L), sat. NaHCO₃ (1 L), and brine (2 L) then it was dried over Na₂SO₄,filtered, and concentrated. The crude material was purified by columnchromatography over SiO₂ gel (100-200 mesh, 80% DCM in hexane) to affordpure(S)-(6-chloro-1-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate (45 g, 84%; e.r=91.4:8.6). ChiralCel® OD-H (250 mm×4.6mm); Mobile Phase: n-Hexane:IPA: 90:10; Run Time: 20 min; flow rate: 1mL/min; sample preparation: IPA. Retention time (major peak)-9.32 min;Retention time (minor peak)-11.46 min).

Step 5: (R)-(6-CHLORO-1-FORMYL-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHYL4-BROMOBENZOATE

To a stirred solution of(S)-(6-chloro-1-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate (100 g, 244.5 mmol) in DCM (2.5 L), Dess-Martinperiodinane (121.4 g, 293.3 mmol) was added at 10° C. The cooling bathwas removed after addition and the reaction mixture was stirred for 30min at ambient temperature. H₂O (9 mL) was then added and the resultingbiphasic mixture was stirred at ambient temperature for 30 min. Thereaction mixture was cooled to 0° C. and quenched with 2 L of a 1:1mixture of 10% Na₂S₂O₃/sat. NaHCO₃ solution. The reaction mixture wasstirred further at ambient temperature for 10 min, then the layers wereseparated and the aqueous layer was extracted with EtOAc (2×1.5 L). Thecombined organic layer was washed with 1 L of 10% Na₂S₂O₃/sat. NaHCO₃solution and 1 L of brine, then it was dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by column chromatography overSiO₂ gel (100-200 mesh, 5% EtOAc/hexane) provided(R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate (80 g, 81%).

The enantiomeric purity of the title compound could be improved by thefollowing procedure:(R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate (190 g) was added in toluene (950 mL) and heated to 50°C. to complete dissolution. The homogeneous solution was cooled toambient temperature and seeded with racemic compound. The solution wascooled to −25° C. and aged overnight. The mother liquor was thendecanted and concentrated to afford 160 g of enantiomerically enriched(R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate (94% ee as determined by chiral HPLC). Chiral HPLCconditions: Column: ChiralCel® OD-H (250 mm×4.6 mm); Mobile Phase:n-Hexane:IPA: 90:10. Run Time: 20 min. Flow rate: 1 mL/min. Samplepreparation: ethanol. Retention time (major peak): 8.488 min (96.97%);Retention time (minor peak): 9.592 min (3.03%).

Step 6:(R)-(6-CHLORO-1-(DIMETHOXYMETHYL)-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHANOL

To a solution of(R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl4-bromobenzoate (75 g, 183.8 mmol) in anhydrous MeOH (1 L), p-TsOH (1 g,9.2 mmol) and trimethyl orthoformate (58.4 mL, 551 mmol) were added andthe reaction mixture was refluxed until the starting material wascompletely consumed (˜4 h). The reaction mass was concentrated to 50%volume and diluted with THF (1 L) and 1N NaOH (1 L, 1 mol). Theresulting reaction mixture was stirred at 40° C. overnight and thenconcentrated under reduced pressure. The residue was diluted with EtOAc(1.5 L). The aqueous layer was separated and extracted with EtOAc (2×500mL) and the combined organic layers were washed with 1N NaOH (1 L) andbrine (1 L), dried over Na₂SO₄ and concentrated under reduced pressure.The crude material was purified by column chromatography over 100-200mesh size SiO₂ gel (10% EtOAc/hexane) to give pure(R)-(6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methanolas a light brown thick oil (44 g, 89%).

Step 7: TERT-BUTYL-4-FLUORO-3-NITROBENZOATE

To a solution of 4-fluoro-3-nitrobenzoic acid (100 g, 540.2 mmol) int-butanol (2.5 L), DMAP (13.18 g, 108.04 mmol) and di tert-butyldicarbonate (248 mL, 1080.4 mmol) were added and the reaction mixturewas heated at 40° C. overnight. Upon completion, the reaction mixturewas diluted with H₂O and the aqueous phase was extracted with EtOAc(3×1.5 L). The combined organic layer was washed further with H₂O (1×1L), brine (1×1 L), and dried over Na₂SO₄. The solvent was removed underreduced pressure and the crude material thus obtained was purified bycolumn chromatography (100-200 mesh size SiO₂ gel, eluting with agradient of 100% hexane to 5% EtOAc in hexane) affording puretert-butyl-4-fluoro-3-nitrobenzoate (70 g, 54%) as light yellow solid.

Step 8: (R)-TERT-BUTYL4-((6-CHLORO-1-(DIMETHOXYMETHYL)-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHOXY)-3-NITROBENZOATE

A solution of(R)-(6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methanol(70 g, 259.2 mmol) in dry THF (3.5 L) was cooled to 0° C. and LiHMDS (1M in THF; 363 mL, 363 mmol) was added dropwise. After 5 min, a solutionof tert-butyl 4-fluoro-3-nitrobenzoate (74.9 g, 311 mmol) in THF (500mL) was added dropwise via dropping funnel and the resulting mixture waswarmed to ambient temperature. Upon completion (˜1 h), the mixture wascooled to 0° C., quenched with sat. NH₄Cl solution (1 L) and extractedwith EtOAc (3×1 L). The combined organic layers were washed with NH₄Cl(1 L) and brine (1 L), dried over Na₂SO₄ and concentrated under reducedpressure. The crude material thus obtained was purified by columnchromatography using 100-200 mesh size SiO₂ gel (5% EtOAc/hexane) toafford (R)-tert-butyl4-((6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoateas yellow thick oil (110 g, 87% yield).

Step 9A:(R)-4-((6-CHLORO-1-FORMYL-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHOXY)-3-NITROBENZOICACID

To a solution of (R)-tert-butyl4-((6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoate(35 g, 71.25 mmol) in MeCN (1 L), erbium triflate (4.3 g, 7.1 mmol) andH₂O (13 mL) were added. The resulting mixture was heated to 80° C.overnight. The solvent was then removed under reduced pressure and theresidue was dissolved in Et₂O (1.5 L) and washed with 1N HCl (500 mL)and brine (500 mL). The organic layer was dried over Na₂SO₄, filtered,and concentrated to afford(R)-4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoicacid (30 g), which was used without further purification.

Alternatively,(R)-4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoicacid may be prepared from(6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl)dimethanol (Step 4) asfollows:

A 250 mL 3-necked-RBF was charged with copper (II) chloride (0.095 g,0.02 eq),2,6-bis((R)-5,5-dibutyl-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine (0.42g, 0.02 eq) and THF (28.5 g, 4V). After insertion with N₂, the batch wasstirred at 20° C. for 0.5 h. To the homogenous green solution was added(6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl)dimethanol (8.0 g, 1.00eq) followed by THF (14.2 g, 2V) and 4-methylmorpholine (3.75 g, 1.05eq). The reaction mixture was cooled to −20° C., and a solution of1-napthoyl chloride (7.06 g, 1.05 eq) in THF (21.3 g, 3 V) was added tothe batch over 0.5 h maintaining the temperature below −15° C. Afteraging at −20° C. for 20 h, an aliquot of the reaction slurry was sampledand assayed by HPLC. The slurry was directly filtered through aglass-fritted funnel while maintaining the temperature at −20° C. Thefilter cake was washed with two portions of cold (<−10° C.) THF (2×14.2g, 2V) rinsed through the reaction vessel. The filter cake(4-methylmorpholine*HCl) was transferred to a labeled container. Themother liquor and washes were concentrated to a minimum volume anddistillative solvent swap by charging toluene until the batch volume is6V and toluene/THF ratio is >98:2 (v/v) as measured by QNMR. To thebatch at 20° C. was added heptane (11 g, 2V) and the slurry was heatedto 85° C. (dissolution observed). The solution was cooled to 75° C. andcharged with seed (0.27 g, 0.02 eq). The slurry was cooled to 20° C.over 3 h and aged for >1 h. The batch was filtered through aglass-fritted filter and the cake was washed with toluene/heptane (3:1v/v) (11 g, 2V) then toluene/heptane (1:1 v/v) (11 g, 2V). The cake wasdried under N₂ for 12 h at ambient temperature and the cake was assayeddry by QNMR (<1 wt % toluene and heptane). The product was obtained asan off-white solid (8.75 g, 63% after wt adjustment).

A 60 L jacketed reactor vented with a bleach scrubber was charged with(S)-(6-chloro-1-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl1-naphthoate (2.693 Kg, 88.6 wt %, 6.3 mol) followed by DCM (17.9 Kg, 5vol) and EtNiPr₂ (2.84 Kg, 3.5 eq). After N₂ inertion, the batch wasagitated and cooled to 0° C. To the alcohol slurry mixture in thereactor was added a solution of freshly prepared sulfur trioxidepyridine (2.10 Kg, 2.5 eq of sulfur trioxide pyridine in 7.43 Kg, 3 vol.DMSO) over 30 min while maintaining the batch temperature below 15° C.After addition, HPLC assay showed >99% conversion. The batch wasquenched by the addition of H₂O (14 L, 5 vol) over −20 min. maintainingthe batch temperature below 15° C. and then toluene (16.8 L, 6 vol) wasadded. After partition, the organic layer was treated with H₂O (14 L, 5vol) and toluene (16.8 L, 6 vol). The top organic layer was washed with2 N HCl twice (14 L each, 5 vol) and brine (14 L, 5 vol). The organiclayer was drained to a clean container, assayed by HPLC and thentransferred back to the clean 60 L reactor through an inline filter. Thebatch was concentrated to a minimal volume and solvent switched to MeOHuntil the batch volume was 28 L (10 vol) and MeOH/toluene ratio was 3:1(v/v) as measured by QNMR. The batch was then transferred to a 30 Ljacketed reactor through an inline filter. After adjustment of the batchtemperature to 30° C., the batch was seeded with the aldehyde (51 g,0.02 eq) as a slurry in MeOH (400 mL). After the slurry was aged for 30min at 30° C., the batch was solvent switched by distillation with MeOHuntil the batch volume is 11 L (4 vol) and MeOH/toluene ratio is ≥99:1(v/v). The batch was then cooled to 5° C. and MeOH/H₂O mixture (3.70 KgMeOH+1.34 Kg H₂O) was added over 1.5 h to bring the total solvent volumeto approximately 5.5 vol and final MeOH/H₂O to 90/10 (v/v). The batchwas heated to 65° C. over 30 min, and cooled to 20° C. over 2 h and agedfor ˜2 h. The batch was filtered through an Aurora® filter fitted with≤25 μm filter cloth. The cake was washed with MeOH/H₂O (10:1) (1×2 vol),then MeOH/H₂O (2:1) (1×2 vol). The cake was dried under N₂ at ambienttemperature for >4 h until dry to give the product as an off-white solid(1.99 Kg, 72% after wt % adjustment).

A 3-necked 250 mL RBF was charged with(R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl1-naphthoate (10 g, 94.4 wt %, 95.3% LCAP, >99% ee), methanol (100 mL),trimethyl orthoformate (7 mL), and TsOH. H₂O (0.24 g). The RBF wasinerted with N₂, and agitation was initiated. The batch was heated to60° C. and aged for 2 h. HPLC assay showed >98% conversion.

The batch was concentrated under vacuum (˜150-190 torr, external temp˜40° C.) to minimal volume using a rotoevaporator. The batch was turnedover to THF by charging THF three times (50 mL each time) and distillingunder vacuum (˜165 torr, external temp ˜40° C.). After each of the firsttwo THF charges, the batch was concentrated down to a minimal volume,and after the last THF charge and distillation QNMR analysis of a sampleshowed the target ratio of >20/1 THF/MeOH (v/v). LiOH.H₂O (10.46 g, 10eq) and H₂O (50 mL) were charged to the 3-necked 250 mL RBF. Thereaction mixture was heated to 65° C. and aged for 18 h. HPLC assayshowed >99% conversion. The batch was cooled to 20° C. and transferredto a 500-mL separatory funnel. MTBE (106 mL) was charged to theseparatory funnel and the funnel was shaken well. After settling for 5min, the bottom aqueous layer was drained. The top organic layer waswashed with 20% K₂CO₃ twice (32 mL and 11 mL). The batch was transferredto a 250 mL RBF. Assay by HPLC showed <2% naphthanoic acid by-product.The batch was concentrated to a minimal volume at reduced pressure onthe rotoevaporator (300 mbar, external temp ˜40° C.). The batch wasturned over to THF using a rotoevaporator (˜250 mbar, external temp ˜40°C.) by adding and distilling THF (˜50 mL, ˜50 mL). After each THFcharge, the batch was distilled down to a minimal volume. THF (50 mL)was charged to the 250 mL RBF. KF of a sample showed 0% H₂O (≤0.1%acceptable). The batch was polish filtered (60 mL medium-frit funnel)into a clean and dry 250 mL 3-necked-RBF using THF (50 mL) for rinsingand volume adjusting. To the batch was added 4-fluoro-3-nitrobenzoicacid (4.61 g, 1.0 eq), the mixture was cooled to −20° C., and 20%potassium tert-butoxide THF solution (40 mL) was added over 1.5 h,maintaining the batch temperature at −20+10° C. (exothermic). Aftercomplete addition, the batch was aged at −20° C. and an aliquot assayedby HPLC after 1.5 h showed 98% conversion. To the batch in the flask wasadded sat. NH₄Cl solution (10 mL), maintaining the temperature at−20±10° C., followed by addition of H₂O (20 mL) and MeTHF (34 mL) at−20±20° C. The mixture was warmed to 20° C. and agitated for 13 h. Thebatch was transferred to a separatory funnel, allowed to settle for ˜5min, and the bottom aqueous layer was removed keeping the rag with theorganic stream. The top organic stream was washed with sat. NH₄Clsolution (10 mL) and H₂O (20 mL) at 20° C. After ˜5 min of settling, theaqueous layer was separated. To the total crude organic stream (KF=14%)was added MSA (4 mL) in a 250 mL 3-necked-RBF. The batch was heated toreflux (65° C.) for 25 h and LC assay showed full conversion (≥97%).

The batch was cooled to <20° C. and K₃PO₄.H₂O (4.5 g) and H₂O (7 mL)were added. The batch was transferred to a separatory funnel and thebottom aqueous layer was drained to give the aldehyde product crudesolution. The combined organic crude stream was concentrated to minimumvolume using a rotary evaporator. To the batch in a 500 mL RBF wascharged AcOH (˜50 mL, ˜50 mL) and distilled using a rotary evaporator atreduced pressure (30 mbar, external temp ˜40° C.). The THF level wasmeasured by QNMR and none was observed. The mixture was transferred to a250 mL 3-necked RBF and AcOH was added to adjust the total volume to ˜40mL, when crystallization occurred. To the batch was added H₂O (12 mL)over ˜1 h. After aging for >1 h, LC assay of supernatant concentrationwas 9 mg/mL. If concentration is >10 mg/mL then a small portion of H₂O(0.2 vol) can be added; after checking by LC, repeat if necessary. Thebatch was filtered, washed with 20% H₂O/AcOH (23 mL) and dried underN₂/vacuum for 3.25 h to give the title compound (8.22 g) as an off-whitesolid (82% yield corrected for purity).

Step 9B: (R)-TERT BUTYL4-((6-CHLORO-1-FORMYL-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHOXY)-3-NITROBENZOATE

To a solution of (R)-tert-butyl4-((6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoate(1 g, 2.033 mmol) in anhydrous acetone (41 mL) was added Amberlyst®-15(1 g, 2.033 mmol; prewashed with 2×10 mL dry acetone). The mixture washeated to 50° C. for 3.5 h, then filtered and rinsed with DCM. Thefiltrate was concentrated and dried under high vacuum overnight (itturned a dark red color). LC/MS and NMR analysis suggested ˜10% ofcorresponding carboxylic acid was present as well as 0.5 eq mesityloxide. The mixture was advanced to Step 11 without further purification.

Step 10:(S)-6′-CHLORO-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLICACID

A solution of crude(R)-4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoicacid (30 g, 77.10 mmol) in AcOH (1 L) was heated to 70° C. and ironpowder (28 g, 500 mmol) was added. The resulting mixture was heated for˜4 h at 70° C. AcOH was then removed under reduced pressure and theresidue was dissolved in DCE (1 L). Sodium triacetoxy borohydride (46.5g, 740 mmol) was added portion-wise and the reaction mixture was stirredat ambient temperature for 1 h. The reaction was then quenched with H₂Ofollowed by 10% aqueous citric acid (500 mL). The aqueous phase wasextracted with DCM (2×1 L) and the combined organic layer was washedwith brine (500 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography using100-200 mesh size SiO₂ gel (40% EtOAc/hexane) to afford pure(S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid as white solid (24 g, 99% after two steps).

Alternatively,(S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid with((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonicacid (1:1) may be prepared as follows:

A pressure reactor was charged with(R)-4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoicacid (20 g, 94 wt %), 5% Pt/S/C wet (2.2 g), THF (400 mL) and titaniumisopropoxide (0.5 mL). The reactor was sealed, purged with inert gas (3cycles, at least once with stirring), and then purged with H₂ (1 cycle).The reactor was pressurized with H₂ to 70 psig, stirring (950 rpm) wasinitiated, and the temperature was increased to 90° C. maintaining theH₂ pressure in the reactor (70 psig at 22-30° C., 80 psig at 50-60° C.and 90 psig at 88-91° C.). After 16 h, the reactor was cooled to ambienttemperature and purged with inert gas (3 cycles). HPLC analysis of thereaction confirmed >98% conversion.

The reaction mixture was filtered through a Celite® pad (2 inch) usingadditional THF for rinses, and the filtrate was concentrated underreduced pressure at 40° C. To the residue was added IPA (60 mL) and 2-4%aqueous MeOH (10 mL). The mixture was stirred for 10 min and then it wasfiltered through a Celite® pad (2 inch). MeOH was evaporated underreduced pressure at 40° C. and to the concentrated IPA solution cooledto ambient temperature was added a solution of +CSA (56.0 g) in IPA (200mL) dropwise over 2 h. After 10% of the CSA solution has been added, themixture was seeded with crystals of the title compound (10-15 mg)followed by the addition of the remaining CSA solution. After stirringat ambient temperature overnight, the mixture was filtered, and thefilter cake was washed with 100 mL of IPA and dried under vacuum/N₂ atambient temperature. The product is isolated as a white solid:(S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid with((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonicacid (1:1) (85-88% yield, >99.5% ee).

Step 11A: (S)-METHYL6′-CHLORO-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

To a solution of(S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (130 g, 379 mmol) in methanol (6 L) was added Amberlyst®-15 (130 g,pre-washed with anhydrous methanol) and heated to reflux for 10 h.Amberlyst® was then removed by filtration and rinsed with methanol(3×300 mL). The combined filtrate was concentrated and the residue waspurified by column chromatography to give pure (S)-methyl6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylateas a white solid (105 g, 77%). Chiral HPLC conditions: Column:ChiralCel® OD-H (250 mm×4.6 mm, 5 μm); Mobile Phase: n-Hexane:EtOH:95:05. Run Time: 25 min. Flow rate: 1 mL/min. Retention time (minorpeak): 10.162 min (1.98%); Retention time (major peak): 12.292 min(98.02%).

Step 11B: (S)-TERTBUTYL6′-CHLORO-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

To a solution of (R)-tert-butyl4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoate(0.9 g, 2.018 mmol) in AcOH (20.22 mL, 353 mmol) at 70° C. was addediron (0.676 g, 12.11 mmol). The mixture was stirred vigorously for 4 h,then concentrated, and the residue was diluted with 20 mL 1,2-DCE.Sodium triacetoxyhydroborate (1.711 g, 8.07 mmol) was added and themixture was stirred at ambient temperature for 20 min. Upon quenching byaddition of 20 mL H₂O, a thick slurry was formed. 20 mL 10% citric acidsolution was added and the mixture became lighter in color. The layerswere separated and the aqueous layer was extracted with 2×20 mL DCM. Thecombined organics were washed with 10 mL 10% citric acid and 10 mLbrine, dried over MgSO₄, filtered, and concentrated. The residue wasdeposited on 3 g SiO₂ gel and purified using 5-10% EtOAc in hexane togive (S)-tert-butyl6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(557 mg, 1.393 mmol, 69.0% yield). Further elution with 30% EtOAc in Hexprovided(S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (132 mg, 0.384 mmol, 19.02% yield).

Step 12: (1R,2S)-1,2-CYCLOBUTANEDIYLDIMETHANOL

To a rapidly stirred solution of LAH (1.0 M solution in THF, 1000 mL,1000 mmol) at ambient temperature in a 3000 mL 3-necked RBF under astream of argon, solid (1R,5S)-3-oxabicyclo[3.2.0]heptane-2,4-dione (40g, 317 mmol) was gradually added over 2 h, maintaining the internaltemperature of the reaction mixture below 50° C. The reaction wasstirred overnight at ambient temperature under argon. After 16 h, thereaction mixture was cooled by an ice bath to 10° C., and, under a faststream of argon, a solution of 36 mL H₂O was added drop wise by additionfunnel at a rate that maintained the temperature between 12-15° C.,approximately 1 mL/min, with vigorous stirring (500 rpm). The mixturewas then vigorously stirred (500 rpm) in the ice-bath for 1 h, thenremoved from the bath and stirred to rt for 1 h before cooling againwith an ice bath to 5-10° C. To the mixture was added 36 mL of a 15%NaOH aqueous solution over a period of 45 min, maintaining thetemperature between 10-20° C. To the mixture was added 108 mL H₂O dropwise by addition funnel, maintaining the temperature between 10-20° C.,over ˜1 h. Upon completed addition of the H₂O, the flask was removedfrom the ice bath, equilibrated to rt and left to stir vigorously underargon overnight. After stirring for 16 h, the mixture was filtered andthe filtrate concentrated under reduced pressure to afford a colorless,slightly opaque oil. The oil was taken up in Et₂O and stirred overanhydrous MgSO₄ and filtered through a pad of Celite®. The filtrateconcentrated under reduced pressure to afford 32.8 g of a colorless oil,which was used in the next step without further purification (89%yield).

Step 13: CIS-CYCLOBUTANE-1,2-DIYLBIS(METHYLENE) DIACETATE

Ac₂O (2.59 mL; 3.0 eq) was added to theCIS-1,2-cyclobutanediyldimethanol (1.06 g, 9.15 mmol) and the resultingsolution was heated to 50° C. After stirring overnight, the mixture wasassayed by GC and showed complete conversion. The mixture was thendiluted with 15 mL of heptane and concentrated under vacuum to give aclear oil. The oil was dissolved in 15 mL heptane and concentrated backdown to an oil (azeotropic removal of Ac₂O) to give the title compoundas an oil (1.827 g, 88% yield, 88.3% purity by QNMR using benzylbenzoate as an internal standard).

Step 14: ((1R,2S)-2-(HYDROXYMETHYL)CYCLOBUTYL)METHYL ACETATE

A 12 L 3-neck-RBF equipped with mechanical stirrer was charged with a 1Msodium citrate solution (prepared by mixing sodium citrate tribasicdihydrate; 682 g, 2320 mmol) and H₂O to reach total volume ˜2.3 L) and3.48 L H₂O (˜25° C.). The mixture was cooled using an ice/H₂O bath to˜20.2° C. pH˜8.46 (measured with pH probe). Amano Lipase fromPseudomonas fluorescens (41.8 g, 1547 mmol) was then added in one charge(pH ˜8.12) and the mixture was vigorously stirred at ambient temperaturefor ˜5 min. (1R,2S)-cyclobutane-1,2-diylbis(methylene) diacetate (348 g,1547 mmol) was added in one charge and the resulting mixture was stirredvigorously at ambient temperature monitoring internal temperature andpH. After stirring the mixture overnight (˜20.9° C. and pH˜5.45) analiquot was collected, extracted with IPAc, diluted with MeCN andanalyzed by GC and the reaction was deemed complete (1.21% SM leftover,0.17% of enantiomer, 1.8% of diol). Celite® (70 g) added to the reactionmixture and the slurry was filtered through a Celite® pad on a mediumporosity glass filter (fast filtration, 15-20 min), rinsing with 2.5 LIPA. The biphasic mixture was transferred into a 12 L-extractor andstirred for 1 min. The aqueous layer was separated and extracted withIPAc (1×4 L), and the combined organic extract was concentrated in vacuoobtaining 337.28 g (99.6% ee; −50-60 mol % of residual IPA by ¹HNMR;QNMR: 37.63 mg+benzyl benzoate (Aldrich catalog #B6630, lot #MKBG9990V,61.27 mg; Result: ˜65 wt %; corrected yield 89%). The crude product wasused as such for the next step.

Step 15: ((1R,2R)-2-FORMYLCYCLOBUTYL)METHYL ACETATE

A 2-L Atlas reactor was charged with((1R,2S)-2-(hydroxymethyl)cyclobutyl)methyl acetate (126.39 g, 79.6 wt %by QNMR; 636 mmol) and 1 L of DCM and the jacket temperature was set to20° C. Iodobenzene diacetate (225 g, 700 mmol) was added as a solid(endothermic addition: the temperature decreased to 15° C.). TEMPO (3.97g, 25.4 mmol) was added as a solid in one portion resulting in a cloudyorange solution, which became clear over the course of 20 min. Afterstirring at 20° C. overnight, an aliquot was collected, diluted withMeOH, and analyzed by GC. An Additional kicker charge of iodobenzenediacetate and TEMPO can be used to push the reaction to completion ifnecessary. The reaction mixture was then cooled to 1.8° C. (internaltemperature, ice/dry ice/H₂O bath) and DIPEA (194 mL, 1113 mol) wasadded drop-wise via addition funnel over 65 min keeping internaltemperature <5° C. The cooling bath was removed and the mixture wasallowed to warm to ambient temperature with stirring. After 48 h analiquot was collected, diluted with methanol, and analyzed by GC showinga 12:1 ratio of trans:cis isomers. The reaction mixture was then cooledto <5° C. (ice/H₂O bath) and H₂O (230 mL) was added over ˜10 min(internal temperature reached 14° C.). The organic layer was separated,washed with H₂O (125 mL) and 1M aqueous NaH₂PO₄ (90 mL) and concentratedin vacuo to afford 273.4 g of ((1R,2R)-2-formylcyclobutyl)methyl acetate(QNMR: 68.85 mg+benzyl benzoate (Aldrich catalog #B6630, Lot #MKBG9990V,72.36 mg). The crude product was used as such for next step.

Step 16:((1R,2R)-2-((R)-(1H-BENZO[D][1,2,3]TRIAZOL-1-YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYLACETATE

To a solution of crude ((1R,2R)-2-formylcyclobutyl)methyl acetate (5 g,10.27 mmol) in 8 mL MTBE was added benzotriazole (1.296 g, 10.00 mmol)as a solid (slightly exothermic). The clear solution became increasinglycloudy and a precipitate formed. The mixture was allowed to equilibrateovernight at ambient temperature then heptane was added (6 mL). Afteraging for 6 h the mixture was filtered at ambient temperature and washedwith 10 mL of 1:1 MTBE/heptane. The white solid was air dried on thefrit under vacuum obtaining 2.48 g of((1R,2R)-2-((R)-(1H-benzo[d][1,2,3]triazol-1-yl)(hydroxy)methyl)cyclobutyl)methylacetate.

Step 17: (S)-METHYL5-(((1S,2R)-2-ACETOXYCYCLOBUTYL)METHYL)-6′-CHLORO-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

((1R,2R)-2-Formylcyclobutyl)methyl acetate (from Step 16; 4.36 g, 27.9mmol) was added to a solution of (S)-methyl6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(5.0 g, 13.97 mmol) (Step 12) in DCM (78 mL) and AcOH (38.8 mL). Thesolution was stirred at ambient temperature for 10 min, then cooled to0° C., and sodium cyanoborohydride (1.463 mL, 27.9 mmol) was addedslowly over 1 h. The mixture was stirred at 0° C. for 10 min, thenpoured slowly into cold NaOH solution, and extracted with EtOAc (120mL). The organic phase was washed with brine, dried over anhydrousNa₂SO₄, and concentrated. The residue was loaded to a 220 g ISCO goldcolumn and eluted with 0% to 10% EtOAc/hexane to provide the titlecompound 6.0 g of the title compound as a white solid. m/z (ESI+ve ion)498.1 (M+H)⁺.

Step 18A: (S)-METHYL6′-CHLORO-5-(((1R,2R)-2-(HYDROXYMETHYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

KOH (0.278 mL, 10.14 mmol) was added to a solution of (S)-methyl5-(((1R,2S)-2-(acetoxymethyl)cyclobutyl)methyl)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(from Step 18; 1.530 g, 3.07 mmol) in MeOH (99 mL). The mixture wasstirred at ambient temperature for 4 h, then neutralized with 1N HCl topH=7, and concentrated under reduced pressure. The aqueous residue wasextracted with EtOAc (400 mL) and the organic extract was washed withbrine, dried over anhydrous Na₂SO₄, and filtered through a short plug ofSiO₂ gel to afford the title compound as a white solid. (1.354 g wasobtained. m/z (ESI, +ve ion) 456.2 (M+H)⁺).

Alternatively, (S)-methyl6′-chloro-5-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylatemay be prepared as follows:

To a slurry of(S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid with((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonicacid (1:1) (Step 11) (32.22 g, 52.5 mmol) and((1R,2R)-2-((R)-(1H-benzo[d][1,2,3]triazol-1-yl)(hydroxy)methyl)cyclobutyl)methylacetate (Step 17) (15.89 g, 57.7 mmol) in DCM (226 mL, 7 mL/g) was addedsodium triacetoxylborohydride (13.90 g, 65.6 mmol) in 4 portions over 30min. Additional((1R,2R)-2-((R)-(1H-benzo[d][1,2,3]triazol-1-yl)(hydroxy)methyl)cyclobutyl)methylacetate (2.89 g, 10.50 mmol) and sodium triacetoxyborohydride (2.78 g,13.12 mmol) were added to drive the reaction to completion (determinedby HPLC assay). 80 mL of H₂O was then added and the resulting mixturewas agitated for 5 min. The layers were separated, the organic phase waswashed with 60 mL H₂O and 20 mL of brine, and then concentrated to anoil under reduced pressure. The residue was dissolved in 50 mL of MeOHand 40 mL of 5N NaOH were then added at ambient temperature(exothermic). Upon reaction completion (determined by HPLC assay), thereaction mixture was partitioned between 133 mL of MTBE and 35 mL of 1.5M citric acid. The organic phase was transferred to a RBF and thesolvent was exchanged to MeCN via atmospheric distillation. Thissolution was seeded at 62° C. (a slurry developed), was allowed to reachambient temperature, and then aged overnight. The slurry was filtered at20.5° C. through a coarse frit glass sinter funnel and the filter cakewas washed using 60 mL of MeCN, then dried in a vacuum oven at 40° C. toconstant weight. Final mass: 21.87 g (96.4 w t % by HPLC).

A 100 mL 3-necked-RBF was charged with(S)-6′-chloro-5-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (4.53 g, 1.0 eq), MeOH (45 mL, 10 vol), and then a preparedsolution of SOCl₂ (11.28 mL, 1.0M in MeCN, 1.1 eq). Under an atmosphereof N₂, the batch was heated to 55° C. and stirred for 18 h (oruntil >99% conversion as determined by HPLC). The reaction mixture wasthen allowed to cool to 20° C. over 2 h. To the resulting white slurrywas added Hunig's base (3.94 mL, 2.2 eq) and after aging for 0.5 h, H₂O(9.0 mL, 2 V) was added as antisolvent over 1 h. The white slurry wasaged for >2 h and the batch was filtered through a glass-fritted filterand the cake was washed with MeOH/H₂O (5:1 v/v) (9.0 mL, 2V) thenMeOH/H₂O (2:1 v/v) (9.0 mL, 2V). The cake was dried under N₂ with vacuumfor 12 h at ambient temperature. The product was obtained as a whitesolid (4.36 g, 92% yield).

Step 18B: (S)-TERTBUTYL6′-CHLORO-5-(((1R,2R)-2-(HYDROXYMETHYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

The title compound was synthesized from (S)-tertbutyl6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(Intermediate AA11A) following the procedures described for IntermediateAA11A, Steps 18-19A).

Step 19A: (S)-METHYL6′-CHLORO-5-(((1R,2R)-2-FORMYLCYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

To a cooled (−70° C.) solution of DMSO (7.12 mL, 2.5 eq) and DCM (183mL, 10 vol) in a 1 L 3-necked-RBF inerted with N₂ was added oxalylchloride (26.1 mL, 1.0M in DCM, 1.3 eq) at a rate to maintaintemperature below −70° C. The batch was aged below −70° C. for 30 minand then a prepared solution of (S)-methyl6′-chloro-5-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(from Step 19A; 18.3 g, 1.0 eq) in DCM (183 mL, 10 vol) was added at arate to maintain reaction temperature <−70° C. The batch was aged for1.5 h and then Et₃N (22.4 mL, 4.0 eq) was added at a rate to maintainbatch temperature <−70° C. After aging for 1 h, the batch was allowed towarm to −20° C. and H₂O (366 mL, 20 vol) was added. The batch wasagitated at 20° C. and the phases separated. The organic layer waswashed with 2×1N HCl (183 mL, 10 vol) and brine (183 mL, 10 vol). Theorganic layer was polish filtered and concentrated in vacuo to afford(S)-methyl6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(19.91 g, 94% yield corrected for wt %) as a tan foam.

Step 19B: (S)-TERTBUTYL6′-CHLORO-5-(((1R,2R)-2-FORMYLCYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

The title compound was synthesized from (S)-tertbutyl6′-chloro-5-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(Intermediate AA 11A, Step 19B) following the procedure described forIntermediate AA11A, step 20A.

Step 20: (S)-METHYL6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

An oven dried 3-necked-RBF equipped with a pressure-equalizing additionfunnel, thermocouple, and magnetic stirbar was cooled to ambienttemperature under a purge of argon gas. The flask was charged with(1R,2S)-2-morpholino-1-phenylpropan-1-ol (40.2 g, 182 mmol; preparedaccording to the literature procedure by Brubaker, J. D.; Myers, A. G.Org. Lett. 2007, 9, 3523-3525) against a positive pressure of argon. Theaddition funnel was charged with toluene (450 mL), which was droppedinto the reactor. The solution was cooled in an ethyleneglycol-CO₂ bath(˜−12° C.) and treated with butyllithium solution (2.5 M in hexane, 72.6mL, 182 mmol), causing a white solid to precipitate that gradually wentinto solution as it was stirred over 30 min. Divinylzinc solution (605mL, 182 mmol; prepared according to Brubaker, J. D.; Myers, A. G. Org.Lett. 2007, 9, 3523-3525. The concentration of divinylzinc solution wasdetermined by titrating against iodine (Krasovskiy, A.; Knochel, P.Synthesis 2006, 890-891; concentration was generally ˜0.25M) was added,and the solution was aged with stirring in the cold bath for 1 h; theinternal temperature was −15° C. (S)-methyl6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(from Step 20A; 48.5 g, 107 mmol) (azeotroped thrice with toluene) wasadded as a solution in toluene (200 mL, 150 mL+2×25 mL cannula/vialrinse) via cannula, over ˜20 min. The internal temperature rose to −10°C. The mixture was stirred for 90 min while maintaining the internalreaction temperature below −5° C. The addition funnel was charged with30% w/w aqueous citric acid (450 mL), then the reaction was quenched byadding the solution to the reaction mixture. The reactor was removedfrom the bath and permitted to stir at ambient temperature. The solutionwas transferred to a separatory funnel and the flask was rinsed withtoluene and 30% aqueous citric acid (50 mL each). The layers were mixedand then separated. The organic layer was washed with H₂O (250 mL), thenbrine (250 mL), and finally dried with MgSO₄. The solution was filteredand concentrated to yield a yellow oil, ˜90 g after vacuum overnight,20:1 dr. This was split into 3 batches and purified by columnchromatography 10 to 20% EtOAc/hexane 1.5 kg SiO₂, to provide(S)-methyl-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(43.3 g, 84%). The aqueous layer and washings were placed in an ice/H₂Obath and basified to pH >13 by addition of 8N aqueous NaOH. Thissolution was then extracted with toluene (3×250 mL). The combinedorganic extracts were washed with H₂O (250 mL) and brine (250 mL), thendried with MgSO₄. The solution was filtered and concentrated to recoverthe ligand in >95% yield.

Step 21:(S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLICACID

To a solution of (S)-methyl6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(from Step 21; 4.59 g, 9.52 mmol) in a mixture of THF (18 mL), MeOH(6.00 mL) and H₂O (6.00 mL) was added LiOH.H₂O (0.799 g, 19.05 mmol) andthe reaction was stirred at 50° C. for 4 h. The reaction mixture wasconcentrated to ˜15 mL, cooled to 0° C. and acidified with 2N HCl topH=3. The resulting viscous oil was diluted with 20 mL of H₂O and 50 mLof EtOAc and a clear two-layer mixture was obtained. More EtOAc (ca. 200mL) was added and the organic layer was separated, washed with brine,dried with MgSO₄, filtered and concentrated under reduced pressure. Thecrude material was loaded onto a column (220 g), and purified with EtOAcin hexane using the following gradient: 0-2.5 min 0% of EtOAc, 2.5-6 min0-20% EtOAc, 6-35 min 20-60% EtOAc, 35-40 min 70% EtOAc to give(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (4.22 g, 9.02 mmol, 95% yield) as a white solid.

Intermediate AA12A(S)-6′-CHLORO-5-(((1R,2R)-2-((S,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLICACID

Step 1A: (S)-METHYL6′-CHLORO-5-(((1R,2R)-2-((S,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

Under argon atmosphere, a dry 3-necked-RBF charged with dry hexane (27mL) was cooled to 0° C. To this solution was added borane-methyl sulfidecomplex (3.29 mL, 34.6 mmol) and cyclohexene (7.01 mL, 69.3 mmol) andthe mixture was stirred at 0° C. for 2 h. To the resulting whitesuspension was added 1-pentyne (3.41 mL, 34.6 mmol) and the mixture wasstirred at ambient temperature for 0.5 h. The mixture was then cooled to−78° C. and diethylzinc, 1.0 M solution in hexane (32.3 mL, 32.3 mmol)was added. After addition the mixture was warmed to 0° C., stirred for 3min then recooled to −78° C. This solution was named solution A. Aseparate flask was charged with a mixture of ((S)-methyl6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(Intermediate AA11A, Step 20A, 5.24 g, 11.54 mmol) and(2s)-3-exo-(morpholino) isobomeal (0.486 g, 2.032 mmol) in hexane (50.9mL) and toluene (16.97 mL). The mixture was stirred at ambienttemperature until all solid was dissolved, then cooled to 0° C. Underargon atmosphere 54 mL of solution A was added slowly via syringe during1.6 h. After stirring for 5 min at 0° C., the mixture was quenched withsat. NH₄Cl solution (70 mL), diluted with H₂O (30 mL) and extracted withEtOAc (3×270 mL), washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was loaded to a 330 g ISCO gold column andeluted with 0% to 5% EtOAc/hexane, to provide the title compound 3.8 gas a white solid. m/z (ESI, +ve ion) 524.1 (M+H)⁺.

Step 1B: (S)-TERTBUTYL6′-CHLORO-5-(((1R,2R)-2-((S,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATEAND (S)-TERTBUTYL6′-CHLORO-5-(((1R,2R)-2-((R,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

The title compound was synthesized from (S)-tert-butyl6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(3.19 g, Intermediate AA11A, Step 20B) following the procedure describedfor Intermediate AA12A, Step 1A. The crude material was absorbed onto aplug of SiO₂ and purified on a 330 g ISCO gold column eluting with 0 to15% EtOAc in heptanes over 45 min to provide (S)-tertbutyl6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(2.36 g). Further elution provided (S)-tert-butyl6′-chloro-5-(((1R,2R)-2-((R,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(0.45 g).

Step 2:(S)-6′-CHLORO-5-(((1R,2R)-2-((S,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLICACID

A mixture of (S)-methyl6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(from Intermediate AA12A, Step A; 4.6 g, 8.78 mmol) and LiOH.H₂O (3.68g, 88 mmol) in MeOH (98 mL) and THF (98 mL) (with a few drops of H₂O)was stirred at 50° C. overnight. The solvent was removed and the residuewas acidified with 1N HCl to pH 2-3. The mixture was extracted withEtOAc (80 mL×3) and the combined organic layer was washed with brine (10mL), dried over anhydrous MgSO₄ and concentrated under reduced pressureto give(S)-6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (4.25 g, 8.34 mmol, 95% yield).

Alternatively, the title compound may be synthesized as follows:

To a solid mixture of (S)-tert-butyl6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(Intermediate AA12A, Step 1B, first eluting isomer, 4.50 g 7.95 mmol)and LiOH.H₂O (1.66 g, 39.7 mmol) was added solvent dioxane/MeOH (1:1)(159 mL). The mixture was heated to 65° C. and stirred overnight. Themixture was then diluted with H₂O and acidified with 1.0 N HCl to pH˜4.The organic solvents were evaporated under reduced pressure and to theresidue was added H₂O. The aqueous mixture was then extracted with EtOActhree times, and the combined organic extract was concentrated. Theresidue was purified on a 120 g SiO₂ gel column eluting with a gradientof 0-70% EtOAc in hexane to provide(S)-6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (3.80 g, 7.45 mmol, 94% yield).

Intermediate AA13A(S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYBUT-3-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLICACID

Step 1A: (S)-METHYL 6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYBUT-3-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

An oven-dried 200-mL flask charged with a suspension of(1R,2R)—N-methyl-1-phenyl-1-(((1S,5S,10R)-10-(trimethylsilyl)-9-borabicyclo[3.3.2]decan-9-yl)oxy)propan-2-amine(5.40 g, 14.54 mmol) in Et₂O (73 mL) under argon was cooled to −78° C.and treated with allylmagnesium bromide (13.22 mL, 13.22 mmol) solution,dropwise. The mixture was allowed to warm to ambient temperature andstirred for 1 h. The solution (˜0.17 M; solution A) was then recooled to−78° C.

A separate 200 mL flask charged with ((S)-methyl6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(Intermediate AA11A, Step 20A, 2.0 g, 4.41 mmol) in Et₂O (22.03 mL)under argon was cooled to −78° C. To this solution was added 40 mL ofthe above-referenced solution A and the resulting mixture was stirred at−78° C. for 40 min. 4-methylmorpholine 4-oxide (3.10 g, 26.4 mmol) wasthen added and the mixture was allowed to warm to ambient temperaturefor 10 min. Methanol (10 mL) was added and the volatile organics wereevaporated under reduced pressure at ambient temperature. Additionalmethanol (100 mL) was added and after stirring at ambient temperaturefor 1 h the mixture was concentrated. The residue was diluted with EtOAc(450 mL), washed with 1N HCl (15 mL), Na₂CO₃ solution (10 mL), and brine(6 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue wasloaded to a 220 g ISCO gold column and eluted with 0% to 5%EtOAc/hexane, to provide 1.88 g of the title compound as a white solid.m/z (ESI, +ve ion) 496.0 (M+H)⁺.

Step 1B: (S)-TERTBUTYL6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYBUT-3-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

The title compound was synthesized from (S)-tert-butyl6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(Intermediate AA11A, Step 20B; 3.0 g) following the procedure describedfor Intermediate AA13A, Step 1A. The crude material was purified on a220 g SiO₂ gel column eluting with 5% EtOAc in hexane over 60 min toprovide (S)-tert-butyl6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxybut-3-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(2.19 g).

Step 2:(S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYBUT-3-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLICACID

A mixture of (S)-methyl6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxybut-3-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(from Intermediate AA13A, Step 1A; 1.88 g, 3.79 mmol) and LiOH solution(1M) (34.1 mL, 34.1 mmol) in MeOH (34 mL) and THF (50 mL) was stirred at65° C. for 50 min. After cooling to ambient temperature, the mixture wasacidified with 1N HCl to pH 2 to 3, extracted with EtOAc (350 mL), driedover anhydrous Na₂SO₄ and concentrated to provide 1.82 g of the titlecompound as a white solid. m/z (ESI, +ve ion) 482.0 (M+H)⁺.

Alternatively, the title compound may be synthesized as follows:

To a solution of (S)-tert-butyl6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxybut-3-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(Intermediate AA13A, Step 1B; 250 mg, 0.465 mmol) in DCM (3.717 mL) atambient temperature, TFA (0.929 mL) was added and the reaction mixturewas stirred for 4 h. The crude reaction mixture was then concentrated,the residue was taken up in EtOAc, washed once with sat. NaHCO₃, driedover MgSO₄, filtered and concentrated to give a white foam. The crudematerial was used as such, without further purification.

Intermediate EE11 N,N-BIS(4-METHOXYBENZYL)AMINE

A solution of 4-methoxybenzaldehyde (Spectrochem; 100 g, 734.5 mmol) and4-methoxybenzyl amine (G.L.R.; 100 g, 734.5 mmol) in toluene (0.8 L) wasrefluxed at 130° C. using a Dean-Stark apparatus for 6 h. The reactionwas monitored by TLC and upon completion, excess solvent was removedunder reduced pressure and the residue was dissolved in methanol (0.8L). The resulting solution was cooled to 0° C. and sodium borohydride(36.12 g, 954.8 mmol) was added in portions. After complete addition,the reaction mixture was stirred for 3 h at ambient temperature.Methanol was removed, and the residue was diluted with H₂O (1.0 L) andEtOAc (2.0 L). The layers were separated and the aqueous layer wasextracted with EtOAc (2×1.0 L). The combined organic layer was washedwith H₂O, brine, and dried over Na₂SO₄. Solvent was removed underreduced pressure and the crude material obtained was purified by columnchromatography over SiO₂ gel (100-200 mesh size) eluting with a gradientof 100% hexane to 25% EtOAc in hexane affording the title compound (160g, 84.6%) as a colorless but opaque liquid.

Intermediate EE12 N,N-BIS(4-METHOXYBENZYL)METHANESULFONAMIDE

A mixture of methanesulfonamide (Sigma-Aldrich, 5 g, 52.6 mmol),p-methoxybenzyl chloride (14.98 mL, 110 mmol), K₂CO₃ anhydrous (36.3 g,263 mmol) and potassium iodide (0.873 g, 5.26 mmol) in anhydrous2-butanone (175 mL) was refluxed (75° C.) overnight. The reaction wasmonitored by TLC and LC/MS and upon completion, the mixture was cooledto ambient temperature, filtered, washed with Et₂O and concentrated. Thecrude material (17.54 g, 52.3 mmol, 99% yield) was used with no furtherpurification. MS (ESI, positive ion) m/z: 358.1 (M+Na).

Intermediate EE13 N,N-BIS(4-METHOXYBENZYL)ETHANESULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EE11; 200g, 775.19 mmol) in DCM (2.5 L) was added Et₃N (336.17 mL, 2325.5 mmol),and the reaction mixture was cooled to 0° C. Ethanesulfonyl chloride (95mL, 1007.75 mmol) was added in drop-wise manner followed by DMAP (19.0g, 155.03 mmol). The resulting reaction mixture was stirred at ambienttemperature for 30 min. The reaction was monitored by TLC and uponcompletion, the mixture was diluted with H₂O and the layers wereseparated and the aqueous phase was extracted with DCM (3×1.5 L). Thecombined organic layer was washed with H₂O, brine, and dried overNa₂SO₄. The solvent was removed under reduced pressure to afford thecrude material which was purified by column chromatography over SiO₂ gel(100-200 mesh), eluting with a gradient of 0-12% EtOAc in hexaneaffording the title compound (145 g, 53.4%) as a white fluffy solid.

Intermediate EE14 N,N-BIS (4-METHOXYBENZYL)PROPANESULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EE11; 405g, 1569.7 mmol) in DCM (4.0 L) was added Et₃N (681.0 mL, 4709.3 mmol),and the reaction mixture was cooled to 0° C. Propanesufonyl chloride(231 mL, 2040.6 mmol) was added in a drop-wise manner followed by DMAP(38.3 g, 313.9 mmol). The resulting mixture was stirred at ambienttemperature for 30 min. The reaction was monitored by TLC and uponcompletion, the mixture was diluted with 2.0 L of H₂O, the layers wereseparated and the aqueous phase was extracted with DCM (3×2.0 L). Thecombined organic layer was washed with H₂O, brine, and dried overNa₂SO₄. The solvent was removed under reduced pressure to afford thecrude material which was purified by column chromatography over SiO₂ gel(100-200 mesh), eluting with a gradient of 0-12% EtOAc in hexaneaffording the title compound (300 g, 52.44%) as white fluffy solid.

Intermediate EE15 BUT-3-ENE-1-SULFONAMIDE

Step 1: SODIUM BUT-3-ENE-1-SULFONATE

A mixture of 4-bromo-1-butene (LLBChem, 3.01 mL, 29.6 mmol) and sodiumsulfite (4.11 g, 32.6 mmol) in H₂O (20 mL) was stirred at 110° C.overnight. The reaction was monitored by TLC and upon completion, H₂Owas removed under reduced pressure and the residue was triturated withacetone. The solid obtained was filtered to afford the title compound asa white solid (4.53 g) which was used as such in next step.

Step 2: BUT-3-ENE-1-SULFONAMIDE

A mixture of sodium but-3-ene-1-sulfonate (4.50 g, 28.5 mmol) andphosphorus oxychloride (70 mL) was stirred at 135° C. for 7 h.Phosphorus oxychloride was then removed under reduced pressure to obtaina dark residue containing a white solid. This residue was diluted withMeCN (20 mL), and then filtered to remove the precipitate. The filtratewas cooled to 0° C. and treated with ammonia solution (30% aqueous) (30mL) dropwise. After complete addition, the reaction was stirred at 0° C.for 30 min. The mixture was diluted with EtOAc (300 mL), washed withbrine, and dried over anhydrous Na₂SO₄. The solvent was removed underreduced pressure and the residue was purified by column chromatographyover SiO₂ gel (100-200 mesh; eluting with 1:1 EtOAc/hexane), affordingthe title compound as a white solid (1.55 g, yield: 40%). MS (ESI,positive ion) m/z: 117.1 (M+1).

Intermediate EE16 N,N-BIS(4-METHOXYBENZYL)BUT-3-ENE-1-SULFONAMIDE

A mixture of but-3-ene-1-sulfonamide (Intermediate EE15; 1.5 g, 11.10mmol), p-methoxybenzyl chloride (3.76 mL, 27.7 mmol), K₂CO₃ anhydrous(7.67 g, 55.5 mmol) and sodium iodide (0.166 g, 1.110 mmol) in anhydrous2-butanone (55.5 mL) was refluxed (75° C.) overnight. The reaction wasmonitored by TLC and LC/MS and upon completion, the mixture was cooledto ambient temperature, filtered, and concentrated. The crude materialwas absorbed onto a plug of SiO₂ gel and purified by chromatographythrough SiO₂ gel (100-200 mesh), eluting with 0 to 30% EtOAc in hexane,to provide the title compound (4.10 g, 10.92 mmol, 98% yield) as acolorless oil. MS (ESI, positive ion) m/z: 376.2 (M+1).

Intermediate EE17 (R)-PENT-4-ENE-2-SULFONAMIDE

Step 1: (S)—N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE-2-SULFONAMIDE AND(R)—N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE-2-SULFONAMIDE

N,N-bis(4-methoxybenzyl)but-3-ene-1-sulfonamide (Intermediate EE16; 50.0g, 133.2 mmol) was azeotroped with toluene and dried under vacuum for 1h. THF (890 mL) was added and the mixture was cooled to −78° C. Butyllithium (2.5 M in hexane, 63.9 mL, 159.9 mmol) was then added and thereaction mixture was stirred at −78° C. for 1 h. This anion solution wasadded slowly to a solution of MeI (16.8 mL, 266.5 mmol) in THF (300 mL)cooled to −78° C. The resulting reaction mixture was stirred for another15 min at −78° C. On completion of the reaction (monitored by TLC) themixture was quenched with sat. NH₄Cl solution and extracted with EtOAc.The organic layer was dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude material which was purified by columnchromatography over SiO₂ gel eluting with 5-10% EtOAc in hexane toprovide the title compound as a racemic mixture (22.0 g) of semisolidnature. Separation of the enantiomers by SFC (Column: Chiralpak® AD-H,50×250 mm, 5 μm; Mobile Phase A: CO₂; Mobile Phase B: Ethanol;Isocratic: 40% B with CO₂ recycler on; Flow Rate: 200 g/min; Loading:2.0 mL of sample prepared as above (˜100 mg); Detection: UV @ 230 nm;Cycle Time: 5 min; Total Elution Time: 10 min; Instrument: Thar 350(Lakers)) provided (S)—N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamideas the first eluting isomer (retention time: 2.22 min) and(R)-N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide as the secondeluting isomer (retention time: 2.57 min).

Step 2: (R)-PENT-4-ENE-2-SULFONAMIDE

To a solution of (R)-N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide(Intermediate EE17, Step 1, second eluting isomer; 221 mg, 0.567 mmol)in DCM (2.8 mL), was added trifluoroacetic acid (1.7 mL, 22.70 mmol)dropwise (the clear solution very rapidly turned dark). After stirringfor 7 h (TLC 30% EtOAc/hexane showed complete loss of starting material)the mixture was diluted with EtOAc, washed with sat. NaHCO₃, backextracted with EtOAc, dried over MgSO₄, and concentrated. The crudematerial was purified via chromatography (12 g ISCO gold column; 0-40%EtOAc in hexane) to provide (R)-pent-4-ene-2-sulfonamide (70 mg, 0.469mmol, 83% yield)

Intermediate EE172 (S)-PENT-4-ENE-2-SULFONAMIDE

This intermediate was synthesized from(S)—N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide (Intermediate EE17,Step 1, first eluting isomer) using the procedure described forIntermediate EE17, Step 2.

Intermediate EE18 (R)-HEX-5-ENE-3-SULFONAMIDE

Step 1: (S)—N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-3-SULFONAMIDE AND(R)—N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-3-SULFONAMIDE

N,N-bis(4-methoxybenzyl)but-3-ene-1-sulfonamide (Intermediate EE16; 40.0g, 106.6 mmol) was azeotroped in toluene under vacuum for 2 h. THF (700mL) was added under argon atmosphere and the reaction mixture was cooledto −78° C. Butyl lithium (2.5 M in hexane; 71.6 mL, 127.9 mmol) wasadded and the reaction mixture was stirred at −78° C. for 1 h. Thisanion solution was added slowly to a solution of ethyl iodide (36.44 mL,340.1 mmol) in THF (40 mL) cooled to −78° C. The resulting reactionmixture was then quenched with sat. NH₄Cl solution, allowed to reachambient temperature and extracted with EtOAc. The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to obtaincrude material which was purified by column chromatography over SiO₂ geleluting with 5-10% EtOAc in hexane to provide the title compound as aracemic mixture (24 g) of semisolid nature. MS (ESI, positive ion) m/z;404.03 (M+1). Separation of the enantiomers by SFC (Sample preparation:14.4 g/200 mL (72 mg/mL) sample solution in MeOH:DCM (3:1); Column:Chiralpak® AD-H, 30×250 mm, 5 μm; Mobile Phase A: CO₂; Mobile Phase B:MeOH (20 mM NH₃); Isocratic: 50% B, Flow Rate: 100 mL/min; OutletPressure: 100 bar; Loading: 1.0 mL of sample solution prepared as above(72 mg); Detection: UV @ 227 nm; Cycle Time: 8 min; Total Elution Time:17 min; Instrument: Thar 350 SFC) provided(S)—N,N-bis(4-methoxybenzyl)hex-5-ene-3-sulfonamide as the first elutingisomer and (R)-N,N-bis(4-methoxybenzyl)hex-5-ene-3-sulfonamide as thesecond eluting isomer.

Step 2: (R)-HEX-5-ENE-3-SULFONAMIDE

This intermediate was synthesized from(R)-N,N-bis(4-methoxybenzyl)hex-5-ene-3-sulfonamide (Intermediate EE18,Step 1, second eluting isomer) using the procedure described forIntermediate EE17, Step 2.

Intermediate EE182 (S)-HEX-5-ENE-3-SULFONAMIDE

This intermediate was synthesized from(S)—N,N-bis(4-methoxybenzyl)hex-5-ene-3-sulfonamide (Intermediate EE18,Step 1, first eluting isomer) using the procedure described forIntermediate EE17, Step 2.

Intermediate EE19 N,N-BIS (4-METHOXYBENZYL)PENT-4-ENE-1-SULFONAMIDE

Step 1: SODIUM PENT-4-ENE-1-SULFONATE®

To a 3 L 3-necked-RBF equipped with a mechanical stirrer, a N₂ gasinlet, a condenser, and a temperature probe was charged5-bromo-1-pentene (Sigma Aldrich, 200 g, 1342 mmol), sodium sulfite(Strem Chemicals; 186 g, 1476 mmol), and H₂O (400 mL). The mixture washeated to reflux (set at 100° C. and refluxed at 93-94° C.) 4 h; aliquotNMR showed >95% conversion. The mixture was concentrated and azeotropedwith acetone to remove H₂O. The crude solid was washed with acetone andfiltered to afford sodium pent-4-ene-1-sulfonate (350 g, 2033 mmol).

Step 2: PENT-4-ENE-1-SULFONAMIDE

To a 3 L 3-necked-RBF equipped with a mechanical stirrer, a N₂ gasinlet, a condenser, and a temperature probe was charged sodiumpent-4-ene-1-sulfonate (100 g, 581 mmol) (˜150 g of crude material fromStep 1) and phosphorus oxychloride (Sigma Aldrich; 532 mL, 5808 mmol).The mixture was heated to 90° C. for 18 h after which the reaction wasfiltered and the solid was washed with MeCN. The organic solution wasconcentrated and azeotroped with MeCN to remove POCl₃ to afford 85 gpent-4-ene-1-sulfonyl chloride intermediate. This material (solution in300 mL MeCN) was charged onto a 1 L 3-necked-RBF equipped with amechanical stirrer, a N₂ gas inlet, a condenser, and a temperatureprobe. The reaction was cooled to 0-5° C. and NH₄OH (Sigma Aldrich; 28%NH₃; 404 mL, 2904 mmol) was added slowly over 30 min. The reaction wasstirred at 0-5° C. for 1 h, after which EtOAc (300 mL) was added and themixture was extracted with EtOAc and concentrated to affordpent-4-ene-1-sulfonamide (50 g, 335 mmol, 57.7% yield) as a brown oil.

Step 3: N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE-1-SULFONAMIDE

The title compound was synthesized from pent-4-ene-1-sulfonamide (4.5 g,30.2 mmol) following the procedure described for Intermediate EE16.Purification of the crude material providedN,N-bis(4-methoxybenzyl)pent-4-ene-1-sulfonamide (11.4 g, 29.3 mmol, 97%yield) as a colorless oil.

Intermediate EE20 (R)-HEX-5-ENE-2-SULFONAMIDE

Step 1: (S)—N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2-SULFONAMIDE AND(R)—N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2-SULFONAMIDE

A solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (IntermediateEE13; 140.0 g, 400.64 mmol) in THF (1.4 L, THF was purged with argon for15 min before using) was cooled to −78° C. and butyl lithium solution(2.6 M in hexane, 200.0 mL, 520.83 mmol) was added drop-wise. Theresulting solution was stirred at −78° C. for 10 min, and4-bromo-1-butene (73.2 mL, 721.15 mmol) was added over 2 min. After 5min, the reaction was allowed to reach ambient temperature and stir for1 h. The reaction was monitored by TLC and upon completion, the mixturewas quenched with sat. NH₄Cl solution (400 mL) and the resulting aqueouslayer was extracted with EtOAc (2×1.0 L). The combined organic layer waswashed with brine and dried over Na₂SO₄. The solvent was removed underreduced pressure to afford the crude material which was purified bycolumn chromatography (SiO₂ gel 100-200 mesh) eluting with a gradient of0-4% acetone in hexane affording the title compound (racemic mixture,80.0 g, 49.5%) as a colorless thick oil. MS (ESI, positive ion) m/z:404.25 (M+1). Separation of the enantiomers by SFC (Sample preparation:75 g/1.5 L (50 mg/mL) sample solution in MeOH; Column: Chiralpak® IF,21×250 mm, 5 μm; Mobile Phase A: CO₂; Mobile Phase B: MeOH(0.2% DEA);Isocratic: 40% B; Flow Rate: 80 mL/min; Outlet Pressure: 100 bar;Loading: 3.0 mL of sample solution prepared as above (150 mg);Detection: UV at 225 nm; Cycle Time: 3.9 min; Total Elution Time: 6 min;Instrument: Thar 80 SFC) provided(S)—N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide as the first elutingisomer and (R)-N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide as thesecond eluting isomer.

Step 2: (R)-HEX-5-ENE-2-SULFONAMIDE

The title compound was synthesized from(R)-N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide (Intermediate EE20,Step 1, second eluting isomer) using the procedure described forIntermediate EE17, Step 2.

Intermediate EE202 (S)-HEX-5-ENE-2-SULFONAMIDE

The title compound was synthesized from(S)—N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide (Intermediate EE20,Step 1, first eluting isomer) using the procedure described forIntermediate EE17, Step 2.

Intermediate EE21 (R)-HEPT-6-ENE-3-SULFONAMIDE

Step 1: (S)—N,N-BIS(4-METHOXYBENZYL)HEPT-6-ENE-3-SULFONAMIDE AND(R)—N,N-BIS(4-METHOXYBENZYL)HEPT-6-ENE-3-SULFONAMIDE

The title compound was synthesized fromN,N-bis(4-methoxybenzyl)propanesulfonamide (Intermediate EE14) using theprocedure described for Intermediate AA20, Step 1. Separation of theenantiomers by SFC (Sample preparation: 40.55 g/170 mL (238.5 mg/mL)sample solution in MeOH; Column: Chiralpak® AD-H, 50×150 mm, 5 μm;Mobile Phase A: CO₂; Mobile Phase B: MeOH (20 mM NH₃); Isocratic: 50% B;Flow Rate: 190 mL/min; Outlet Pressure: 100 bar; Loading: 1.5 mL ofsample solution prepared as above (357.8 mg); Detection: UV at 227 nm;Cycle Time: 17.5 min; Total Elution Time: 21 min; Instrument: Thar 350SFC) provided (S)—N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide asthe first eluting isomer and(R)-N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide as the secondeluting isomer.

Step 2: (R)-HEPT-6-ENE-3-SULFONAMIDE

The title compound was synthesized from(R)-N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide (Intermediate EE21,Step 1, second eluting isomer) using the procedure described forIntermediate EE17, Step 2.

Intermediate EE212 (S)-HEPT-6-ENE-3-SULFONAMIDE

The title compound was synthesized from(S)—N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide (Intermediate EE21,Step 1, first eluting isomer) using the procedure described forIntermediate EE17, Step 2.

Intermediate EE22 (2R,3 S)-3-METHYLHEX-5-ENE-2-SULFONAMIDE

Step 1: (4S,5S)-4,5-DIMETHYL-1,3,2-DIOXATHIOLANE 2,2-DIOXIDE

To a 500-mL, 3-necked-RBF (equipped with a H₂O-cooled reflux condenserand an HCl trap) was added (2s,3s)-(+)-2,3-butanediol (Aldrich; 15.00mL, 166 mmol) and CCl₄ (120 mL). SOCl₂, reagentplus (14.57 mL, 200 mmol)was then added drop wise via a syringe over a period of 20 min and theresulting mixture was heated to 98° C. for 45 min, then allowed to coolto rt. The reaction mixture was then cooled in an ice/H₂O bath, MeCN(120 mL) and H₂O (150 mL) were added followed by ruthenium(III) chloride(0.035 g, 0.166 mmol). Sodium periodate (53.4 g, 250 mmol) was thenadded slowly portion wise over 30 min. The resulting biphasic brownmixture was stirred vigorously while allowed to reach rt for a period of1.5 h (internal temperature never increased above rt). TLC (50% EtOAc inheptanes) showed complete conversion. The crude mixture was then pouredinto ice H₂O and extracted twice with 300 mL of Et₂₀. The combinedorganic layers were washed once with 200 mL of sat. sodium bicarbonate,washed once with 200 mL of brine, dried over Na₂SO₄, and concentrated byrotary evaporation to give (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane2,2-dioxide (21.2 g, 139 mmol) as a red oil.

Step 2: (2S,3S)-3-METHYLHEX-5-EN-2-OL

To a 500 mL flask was added (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane2,2-dioxide (from Intermediate EE22, Step 1; 21.2 g, 139 mmol) and THF(220 mL) at which time the solution was cooled to −78° C. and wassubjected to 3 cycles of evacuation/back-filling with argon. To thesolution was added dilithium tetrachlorocuprate(ii), 0.1M solution inTHF (69.7 mL, 6.97 mmol). The resulting mixture was stirred at −78° C.for 30 min and then allylmagnesium bromide, 1.0 M solution in Et₂O (397mL, 397 mmol) was added slowly via cannula over 80 min. The resultingmixture was stirred at 0° C. for 4 h. The mixture was quenched with 200mL H₂O and allowed to reach rt at which time the volatiles were removedby rotary evaporation. To the aqueous residue was then added 50% H₂SO₄(150 mL), the mixture was stirred for 5 min, Et₂O was then added (400mL) and the mixture was stirred vigorously at rt overnight. The layerswere separated; the aqueous layer was extracted with 300 mL Et₂O and thecombined organic layers were washed with 300 mL of sat. NaHCO₃, driedover Na₂SO₄, filtered and concentrated by rotary evaporation to give(2S,3S)-3-methylhex-5-en-2-ol (6.7 g, 58.7 mmol) as a clear oil.

Step 3: 2-(((2R,3S)-3-METHYLHEX-5-EN-2-YL)THIO)PYRIMIDINE

To a 2000 mL dry RBF containing a stirring solution of tributylphosphine(57.7 mL, 231 mmol) in 1000 mL degassed THF (sparged with argon for 30min plus 5 cycles of pump/add argon) at 0° C. was added diethylazodicarboxylate (40 wt. % solution in toluene; 103 mL, 262 mmol) dropwise under an atmosphere of argon. A solution of(2S,3S)-3-methylhex-5-en-2-ol (from Intermediate EE22, Step 2; 17.6 g,154 mmol; dried over Na₂SO₄) was added drop wise as a solution in 50 mLof THF to the solution of phosphine/diethyl azodicarboxylate complex,via syringe-filter (0.45 um). The resulting ROH/diethylazodicarboxylate/tri-n-butylphosphine mixture was aged at zero degreesfor 15 min (solution turned light orange), at which timepyrimidine-2-thiol (49.3 g, 439 mmol) was added gradually to the top ofthe reaction vessel (as a solid) under positive argon pressure. Thereaction was stirred at 0° C. for 1 h then at rt 15 h (reaction notcomplete at 12 h by LC/MS). The crude reaction was then filtered toremove excess pyrimidine-2-thiol, diluted with 1000 mL of EtOAc,extracted twice with 500 mL of 1 N K₂CO₃, and once with 500 mL of brine.The aqueous layer was back extracted with 300 mL of EtOAc and thecombined organic layers were dried over Na₂SO₄. The organic solution wasthen filtered, the solvent removed by rotary evaporation and the crudefiltered to remove the (E)-diethyl diazene-1,2-dicarboxylategenerated inthe reaction. The filtrate (125 g) was passed through a SiO₂ plug (500 gSiO₂, eluting with 2 L of DCM) to give 75 g of crude product aftersolvent removal. The crude product was purified again on a Combiflash®(125 g gold SiO₂ column), eluting with 10% EtOAc in heptanes to give2-(((2R,3S)-3-methylhex-5-en-2-yl)thio)pyrimidine (20.37 g, 98 mmol) asa light yellow oil.

Step 4: 2-(((2R,3S)-3-METHYLHEX-5-EN-2-YL)SULFONYL)PYRIMIDINE

To a 500 mL 3-necked-RBF with a reflux condenser was addedphenylphosphonic acid (3.95 g, 24.96 mmol), sodium tungstate oxidedihydrate (8.23 g, 24.96 mmol), tetrabutylammonium sulfate (50 wt. %solution in H₂O, 28.7 mL, 24.96 mmol), a catalytic amount of hydrogenperoxide (30% in H₂O, 12.75 mL, 125 mmol), toluene (200 mL) and2-(((2R,3S)-3-methylhex-5-en-2-yl)thio)pyrimidine (from IntermediateEE22, Step 3; 52 g, 250 mmol). The reaction was stirred at 45° C. for 5min at which time hydrogen peroxide 30% in H₂O (58.6 mL, 574 mmol) wasadded portion wise (10 mL at a time). Five min after the first portionof hydrogen peroxide was added, an exotherm was observed (65° C.), thereaction was taken out of oil bath, the addition was stopped and theflask placed in a H₂O bath until temperature stabilizes. The flask wastaken out of the H₂O bath and the portion wise addition of hydrogenperoxide was continued at a rate in which the internal temperaturestayed between 45° C. and 55° C. (˜40 min). An ice bath was utilized ifthe temperature went above 60° C. and an oil bath was used if thetemperature fell below 45° C. The reaction was then stirred at 45° C.for 1 h. The reaction was diluted with 1400 mL of EtOAc and extractedtwo times with 500 mL of H₂O and once with 500 mL of brine. The organiclayer was dried over Na₂SO₄, filtered, concentrated, and the crudepurified on a Combiflash® (330 g gold SiO₂ column per 30 grams ofcrude), eluting with 0%-50% EtOAc in heptanes to give 2-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)pyrimidine (55.7 g, 232 mmol) as alight yellow oil.

Step 5: SODIUM (2R,3S)-3-METHYLHEX-5-ENE-2-SULFINATE

To a solution of 2-(((2R,3 S)-3-methylhex-5-en-2-yl)sulfonyl)pyrimidine(from Intermediate EE22, Step 4; 52 g, 216 mmol) in MeOH (400 mL) at rtwas added sodium methoxide solution (51.0 mL, 223 mmol) over 70 min. Thesodium methoxide was added portion wise, the internal temperature wasmonitored, and the addition was slowed or the reaction was cooled in aH₂O bath, never letting the internal temperature exceeded 30° C. Themixture was concentrated by rotary evaporation and the waxy solid wastriturated with MTBE (add 200 mL MTBE, stir for 1 h using a spatula tobreak up clumps), filtered (use a stream of N₂ over filter cake), andwashed with 100 mL of cold MTBE to obtain sodium(2R,3S)-3-methylhex-5-ene-2-sulfinate (46 g, 250 mmol) as a an off whitesolid.

Step 6: (2R,3S)-3-METHYLHEX-5-ENE-2-SULFONAMIDE

To a 1000 mL 3-necked-RBF was added sodium(2R,3S)-3-methylhex-5-ene-2-sulfinate (from Intermediate EE22, Step 5;46 g, 225 mmol), 500 mL of H₂O and KOAc (44.1 g, 449 mmol) at rt. Theflask was place in a 45° C. oil bath and hydroxylamine-O-sulfonic acid(21.09 g, 187 mmol) was added portion wise over 90 min. The internaltemperature of the reaction was monitored and the reaction was removedfrom the oil bath (if needed) to control exotherm (Tmax=55° C.). Thereaction was monitored by LC/MS every 10 min and was complete after theaddition of 0.83 eq. of hydroxylamine-O-sulfonic acid. The mixture wasthen cooled to rt and was extracted with 1000 mL of EtOAc. The organicphase was extracted three times with 500 mL of 1 N HCl, two times with300 mL of sat. sodium bicarbonate, once with 200 mL of brine, dried overNa₂SO₄, filtered, and concentrated by rotary evaporation to provide(2R,3S)-3-methylhex-5-ene-2-sulfonamide (32 g, 181 mmol) as a whitesolid.

Intermediate 1(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^(3,6).0^(19,24)]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

Step 1:(S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(((2R,3S)-3-METHYLHEX-5-EN-2-YL)SULFONYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXAMIDE

DMAP (3.42 g, 28.0 mmol) was added to a solution of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (Intermediate AA11A; 7.7 g, 16.45 mmol) and(2R,3S)-3-methylhex-5-ene-2-sulfonamide (Intermediate EE22; 5.83 g, 32.9mmol) in DCM (411 mL) cooled to 0° C. EDC hydrochloride (6.31 g, 32.9mmol) was then added slowly portionwise. The mixture was stirred whileallowing to reach ambient temperature overnight. The mixture was washedwith 1N HCl and brine and the aqueous layer was back-extracted withEtOAc. The combined organics were dried over MgSO₄, filtered andconcentrated. The yellow oily residue was loaded onto a 220 ISCO goldcolumn and purified eluting with 0% to 20% EtOAc (containing 0.3%AcOH)/heptanes, to provide(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide(7.89 g, 12.58 mmol, 76% yield).

Step 2:(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^(3,6).0^(19,24)]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE13′,13′-DIOXIDE

To a 20 L reactor blanketed in argon was charged 14 L of 1,2-DCE.(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide(18.75 g, 29.9 mmol) was added as a solution in 400 mL 1,2-DCE followedby a 400 mL rinse. The reactor was sealed and purged with argon.Hoveyda-Grubbs II (1.873 g, 2.99 mmol) was added as a solution in 150 mLof 1,2-DCE followed by a 50 mL rinse. The reactor was heated to 60° C.over 1 h with an argon sweep of the headspace and held at temperaturefor 9 h. The reaction was quenched by the addition of2-(2-(vinyloxy)ethoxy)ethanol (1.501 g, 11.36 mmol), cooled to ambienttemperature, and concentrated to ˜200 mL volume by rotary evaporation.The reaction was transferred to a 1 L RBF and diluted to 500 mL volumewith 1,2-DCE. The reaction was treated with 52 g of Silicycle Si-Thiol(SiliCycle Inc., Quebec City, Quebec CANADA Cat# R51030B) with stirringfor 9 h at 40° C., filtered and rinsed with 2×65 mL DCM. The solutionwas passed through a Whatman GF/F filter cup (GE Healthcare Bio-SciencesPittsburgh, Pa., USA) to afford a transparent yellow solution. Thereaction was concentrated to afford a crude product mass of 27.4 g. Theresidue was slurried in 250 mL IPAc and evaporated to dryness threetimes. The reaction was suspended in 270 mL IPAc, heated to dissolution,allowed to cool to ambient temperature, and stirred for 18. The solidswere filtered and washed with 65 mL IPAc. The solid was air-dried for 30min then placed under high vacuum for 3 h to afford 12.56 g of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0^(3,6).0^(19,24)]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide which is 91.7% by weight. ¹H NMR (500 MHz, CD₂Cl₂) δ8.06 (s, 1H), 7.71 (d, J=8.56 Hz, 1H), 7.17 (dd, J=8.44, 2.32 Hz, 1H),7.09 (d, J=2.20 Hz, 1H), 6.91 (s, 3H), 5.81 (ddd, J=14.92, 7.82, 4.16Hz, 1H), 5.71 (dd, J=15.41, 8.31 Hz, 1H), 4.16-4.26 (m, 2H), 3.83 (d,J=14.43 Hz, 1H), 3.69 (d, J=14.43 Hz, 1H), 3.25 (d, J=14.43 Hz, 1H),3.04 (dd, J=15.28, 9.66 Hz, 1H), 2.68-2.84 (m, 2H), 2.41 (app qd,J=9.80, 3.70 Hz, 1H), 2.25-2.34 (m, 1H), 1.93-2.00 (m, 5H), 1.74-2.11(m, 9H), 1.62-1.73 (m, 1H), 1.43 (d, J=7.09 Hz, 3H) 1.35-1.42 (m, 1H)1.03 (d, J=6.60 Hz, 3H). MS (ESI, +ve ion) m/z 599.2 (M+H)⁺.

Intermediate 2(1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^(3,6).0^(19,24)]PENTACOSA[16,18,24]TRIEN]-15′-ONE13′,13′-DIOXIDE

A mixture of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0^(3,6).0^(19,24)]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (Intermediate 1, 7.5 mg, 0.013 mmol) and platinum (IV)oxide (2.84 mg, 0.013 mmol) in EtOAc (1.536 mL) was stirred under anatmosphere of H₂ (balloon) at ambient temperature for 45 min. Thereaction mixture was then filtered through a syringe filter. The crudematerial was purified by chromatography through a Redi-Sep® pre-packedSiO₂ gel column (4 g), eluting with 15% to 50% EtOAc (containing 0.3%AcOH)/heptanes, to provide the title product. ¹H NMR (400 MHz, CD₂Cl₂) δ8.24 (br. s., 1H), 7.71 (d, J=8.4 Hz, 1H), 7.17 (dd, J=2.3, 8.4 Hz, 1H),7.09 (d, J=2.2 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 6.99 (dd, J=2.0, 8.0 Hz,1H), 6.93 (d, J=8.2 Hz, 1H), 4.10 (s, 2H), 4.05 (ddd, J=1.2, 7.2, 14.3Hz, 1H), 3.82 (d, J=15.3 Hz, 1H), 3.74-3.69 (br. S., 1H), 3.68 (d,J=14.3 Hz, 1H), 3.23 (d, J=14.3 Hz, 1H), 3.06 (dd, J=7.3, 15.4 Hz, 1H),2.84-2.68 (m, 2H), 2.38 (d, J=3.5 Hz, 2H), 2.08-1.96 (m, 3H), 1.96-1.88(m, 1H), 1.88-1.75 (m, 2H), 1.74-1.56 (m, 4H), 1.47 (d, J=12.1 Hz, 2H),1.40 (d, J=7.2 Hz, 3H), 1.32-1.26 (m, 2H), 1.23-1.15 (m, 2H), 1.00 (d,J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 601.2 (M+H)⁺.

Intermediate 3(1S,3′R,6′R,8′E,12′S)-6-CHLORO-12′-METHYL-3,4-DIHYDRO-2H,7′H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^(3,6).0^(19,24)]PENTACOSA[8,16,18,24]TETRAENE]-7′,15′-DIONE13′,13′-DIOXIDE

The allyl alcohol (310 mg, 0.520 mmol, Intermediate 1) was dissolved inDCM (6.0 mL) and cooled to 0° C. Dess-Martin periodinane (270 mg, 0.63mmol) was then added and the reaction mixture was stirred for 1.5 hours.Another 90 mg of Dess-Martin reagent was added at 0° C. and stirred foran additional 45 minutes. The reaction was quenched with 20 mL of 1MNa₂S₂O₃ and allowed to warm to room temperature. The mixture wasextracted (3×40 mL) with DCM. The combined organic layers were washedwith water (1×30 mL) and then dried over magnesium sulfate. The crudeproduct was purified by medium pressure chromatography (silica, 10 to100% EtOAc (+0.3% HOAc):Hexanes) to give (1S,3′R,6′R,8′E,12′S)-6-chloro-12′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0^(3,6).0^(19,24)]pentacosa[8,16,18,24]tetraene]-7′,15′-dione13′,13′-dioxide (230 mg, 0.385 mmol, 74.0% yield). ¹H NMR (400 MHz,CDCl₃) δ 8.32-9.05 (m, 1H), 7.69-7.90 (m, 1H), 7.35-7.48 (m, 1H),7.17-7.27 (m, 1H), 7.06-7.16 (m, 1H), 6.81-6.99 (m, 2H), 6.59-6.72 (m,1H), 5.93 (d, J=15.65 Hz, 1H), 4.01-4.24 (m, 3H), 3.74-3.97 (m, 3H),3.26 (d, J=14.48 Hz, 1H), 2.92-3.16 (m, 2H), 2.69-2.89 (m, 2H),1.70-2.26 (m, 9H), 1.48-1.56 (m, 3H), 1.35-1.46 (m, 1H), 1.29 (t, J=7.14Hz, 1H), 1.07-1.19 (m, 3H). m/z (ESI, +ve ion) 596.7 (M+H)⁺.

Intermediate 4(1S,3′R,6′R,11′S,12′R)-6-CHLORO-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,7′H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^(3,6).0^(19,24)]PENTACOSA[16,18,24]TRIENE]-7′,15′-DIONE13′,13′-DIOXIDE

To a solution of(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide (1.20 g, 2.02 mmol, Intermediate 1) in EtOAc (50 mL) wasadded platinum (IV) oxide (92 g, 0.40 mmol) and the reaction was fittedwith a H₂ balloon and stirred vigorously for 15 h. The reaction mixturewas filtered through Celite and concentrated. The concentrate wasdissolved in dichloromethane (20 mL) and then Dess-Martin periodinane(0.95 g, 2.2 mmol) was added in four portions over 5 min at 0° C. Afterthe reaction was stirred at 0° C. for 15 min, the reaction was quenchedwith 1N sodium thiosulfate solution at 0° C. (10 mL) and stirredvigorously at rt for 30 min. Then the reaction mixture was extracted(EtOAc). The separated organic layer was washed (brine), dried (Na₂SO₄),and concentrated under reduced pressure. The residue was purified bysilica-gel chromatography (0% to 25% EtOAc/hexane, 0.1% AcOH) to provide(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0^(3,6).0^(19,24)]pentacosa[16,18,24]triene]-7′,15′-dione13′,13′-dioxide as a solid (0.85 g, 70% yield). MS (ESI, +ve ion) m/z599.2 (M+H)⁺.

Biological Assays

Cell Free Mcl-1:Bim Affinity Assay (Mcl-1 HTRF)

The inhibition of the Mcl-1/Bim interaction was measured using atime-resolved fluorescence resonance energy transfer (TR-FRET) assay.The recombinant human Mcl-1 (C-terminally 6×His tagged Mcl-1 containingresidues 171-327) was generated at Amgen Inc (Thousand Oaks, Calif.). Abiotinylated peptide derived from human Bim (residues 51-76) waspurchased from CPC Scientific (San Jose, Calif.). The TR-FRET assay wasconducted in a 384-well white OptiPlate™ (PerkinElmer, Waltham, Mass.)in a total volume of 40 μL. The reaction mixture contained 0.1 nM Mcl-1(171-327), 0.05 nM biotin-Bim(51-76), 0.05 nM LANCE® Eu-W1024 Anti-6×His(PerkinElmer), 0.072 nM Streptavidin-Xlent (Cisbio, Bedford, Mass.), andserially diluted test compounds in the binding buffer of 20 mM Hepes, pH7.5, 150 mM NaCl, 0.016 mM Brij®35, and 1 mM dithiothreitol. Testcompounds were pre-incubated with Mcl-1 (171-327) and biotin-Bim (51-76)for 60 min before addition of the detection mixture (LANCE® Eu-W1024Anti-6×His and Streptavidin-Xlent). The reaction plates were furtherincubated overnight and then were read on an Envision® multimode reader(PerkinElmer). Fluorescence signals were measured at 620 nm (40-nmbandwidth) and 665 nm (7.5-nm bandwidth) with a 60 is delay afterexcitation at 320 nm (75-nm bandwidth). The signal ratio at 665/620 nmcorresponded to the Mcl-1/Bim interaction and was used in all dataanalyses. The IC₅₀ values of test compounds were determined fromduplicate data by analyzing competition curves using a four-parametersigmoidal model in GraphPad Prism (GraphPad Software, San Diego, Calif.)or in Genedata Screener® (Genedata, Basel, Switzerland).

Cell Viability Assay (OPM-2 10 FBS)

The human multiple myeloma cell line, OPM-2, was cultured in completegrowth medium containing RPMI 1640 and 10% fetal bovine serum (FBS).Cells were seeded into 384-well plates at 3000 cells/well density incomplete growth medium containing 10% FBS, and incubated for 16 h withserially diluted test compounds in a 37° C. incubator with 5% CO₂. Cellviability was tested using CellTiter-Glo® assay (Promega, Madison, Wis.)according to the manufacturer recommendations. Luminescence wasdetermined using an EnVision® Multilabel plate reader 25 min after theaddition of detection reagent. IC₅₀ values were then calculated withXlfit using a logistical 4-parameter fit model in GraphPad Prism(GraphPad Software, San Diego, Calif.) or in Genedata Screener®(Genedata, Basel, Switzerland).

Results for compounds tested in these biological assays are set forthbelow in Table 4 and Table 5.

TABLE 4 Example Mcl-1 HTRF OPM-2 10% Number IC₅₀ (μM) FBS IC₅₀ IP (μM) 10.000086 0.085 2 0.000109 0.076 3 0.000094 0.060 4 0.000116 0.094 50.000098 0.040 6 0.000079 0.076 7 0.000058 0.025 8 0.000053 0.025 90.000078 0.050 10 0.000103 0.075 11 0.000098 0.051 12 0.000072 0.022 130.000094 0.063 14 0.000080 0.059 15 0.000119 0.071 16 0.000065 0.053 170.000073 0.034 18 0.000060 0.022 19 0.000125 0.047 20 0.000082 0.022 210.000156 0.047 22 0.000669 2.230 23 0.000071 0.024 24 0.000086 0.035 250.000113 0.041 26 0.000079 0.032 27 0.000095 0.029 28 0.000082 0.111 290.000249 0.186 30 0.000110 0.166 31 0.000184 0.216 32 0.000128 0.147 330.008250 5.570 34 0.000495 0.379 35 0.000218 0.235 36 0.000554 0.518 370.000615 0.643 38 0.000342 0.489 39 0.000377 0.389 40 0.000444 0.571 410.000642 0.810 42 0.000170 0.149 43 0.001640 0.888 44 0.000288 1.360 450.000245 0.891 46 0.000107 0.167 47 0.000131 0.285 48 0.000140 0.407 490.000087 0.185 50 0.000736 1.530 51 0.000072 0.099 52 0.000522 0.330 530.000336 0.290 54 0.000173 0.129 55 0.000162 0.080 56 0.000083 0.079 570.000258 0.090 58 0.000719 0.095 59 0.000116 0.048 60 0.000287 0.129 610.000075 0.124 62 0.000115 0.110 63 0.000173 0.582 64 0.000126 0.201 650.000451 1.500 66 0.000246 0.318 67 0.000197 0.149 68 0.000397 1.520 690.003830 1.480 70 0.001326 3.140 71 0.000371 1.140 72 0.000800 0.185 730.000609 0.129 74 0.002290 3.360 75 0.002047 1.610 76 0.003815 0.670 770.001217 0.415 78 0.000573 0.175 79 0.001800 0.245 80 0.001550 0.205 810.000140 0.112 82 0.000394 0.520 83 0.000223 0.245 84 0.000106 0.061 850.000491 0.274 86 0.00390 7.95 87 0.000127 0.141 88 0.000139 0.074 890.003750 8.210 90 0.004660 8.980 91 0.000203 0.559 92 0.000143 0.199 930.000530 0.924 94 0.000191 0.140 95 0.000189 0.338 96 0.000114 0.111 970.000299 0.228 98 0.000373 0.183 99 0.000243 0.310 100 0.000188 1.650101 0.000196 0.263 102 0.000182 0.416 103 0.000452 0.737 104 0.0011190.782 105 0.000423 0.655 106 0.000299 0.308 107 0.001138 0.872 1080.000198 0.116 109 0.001042 0.916 110 0.000505 1.720 111 0.000362 0.301112 0.000617 0.654 113 0.001190 1.330 114 0.000104 0.068 115 0.0013700.686 116 0.000244 0.387 117 0.000352 0.358 118 0.000215 0.558 1190.000465 0.694 120 0.000263 0.304 121 0.000084 0.120 122 0.000087 0.138123 0.000205 0.228 124 0.000646 0.598 125 0.006100 1.475 126 0.0006270.900 127 0.000395 6.120 128 0.000256 19.600 129 0.001694 2.630 1300.000920 1.580 131 0.000249 0.482 132 0.000613 0.263 133 0.000189 0.136134 0.004640 3.000 135 0.008175 >33.3 136 0.004700 1.020 137 0.0047401.150 138 0.026700 >33.3 139 0.032017 >33.3 140 0.000098 0.125 1410.000152 0.367 142 0.000157 0.174 143 0.000432 0.219 144 0.000271 0.163145 0.000124 0.113 146 0.000337 0.150 147 0.000376 0.157 148 0.0012001.610 149 0.000128 0.119 150 0.000193 0.245 151 0.000843 0.462 1520.000092 0.110 153 0.000960 10.800 154 0.000197 0.554 155 0.000228 0.378156 0.000096 0.062 157 0.000126 0.121 158 0.000092 0.018 159 0.0000960.079 160 0.000221 0.148 161 0.000094 0.113 162 0.000072 0.055 1630.000179 0.130 164 0.000047 0.031 165 0.000190 0.182 166 0.000107 0.050167 0.000086 0.052 168 0.000138 0.052 169 0.000140 0.074 170 0.0001310.075 171 0.000074 0.122 172 0.000137 0.055 173 0.000173 0.323 1740.000322 0.639 175 0.000069 0.064 176 0.000118 0.149 177 0.000153 0.615178 0.000177 0.071 179 0.000072 0.036 180 0.000106 0.081 181 0.0003240.074 182 0.000171 0.088 184 0.000068 0.017 185 0.000170 1.060 1860.000255 0.431 187 0.000066 0.043 188 0.000084 0.038 189 0.000084 0.033190 0.000087 0.053 191 0.000096 0.042 192 0.000078 0.065 193 0.0000960.023 194 0.000148 0.054 195 0.000214 0.065 196 0.000470 0.304 1970.000364 0.129 198 0.000181 1.314 199 0.000119 0.208 200 0.000315 0.583201 0.000119 0.244 202 0.000058 0.142 203 0.000113 0.112 204 0.0002300.319 205 0.000263 0.437 206 0.000223 6.300 207 0.000137 0.395 2080.000099 0.368 209 0.000552 0.437 210 0.000138 0.185 211 0.000147 0.156212 0.000122 0.307 213 0.000239 0.400 214 0.000071 0.084 215 0.0001490.107 216 0.000490 0.183 217 — 0.192 218 0.000142 0.092 219 0.0000730.047 220 0.000052 0.042 221 0.000069 0.120 222 0.000080 0.118 2230.000251 0.258 224 0.000127 0.157 225 0.000087 0.280 226 0.000057 0.049227 0.000207 0.131 228 0.000200 0.0931 229 0.000619 0.096 230 0.0000510.070 231 0.000061 0.098 232 0.000141 0.200 233 0.000516 0.202 2340.000163 0.071 235 0.000180 0.120 236 0.000097 0.087 237 0.000130 0.064238 0.000176 0.076 239 0.000146 0.148 240 0.000128 0.141 241 0.0001500.137 242 0.000249 0.791 243 0.000078 0.106 244 0.001654 0.638 2450.000120 0.058 246 0.000099 0.138 247 0.000129 0.107 248 0.000222 0.518249 0.000063 0.114 250 0.000071 0.047 251 0.002260 3.870 252 0.0013751.800 253 0.000804 0.887 254 0.001200 0.544 255 0.001740 1.480 2560.000433 1.640 257 0.000403 0.981 258 0.000069 0.095 259 0.000230 0.254260 0.000083 0.103 261 0.000153 0.146 262 0.000093 0.089 263 0.0001470.124 264 0.000396 0.771 265 0.000423 0.578 266 0.000282 0.723 2670.000297 0.250 268 0.000065 0.072 269 0.000104 0.086 270 0.000035 4.860271 0.000031 0.359 272 0.000144 0.137 273 0.000494 0.501 274 0.0002850.232 275 0.000176 0.082 276 0.000096 0.110 277 0.000058 0.057 2780.000039 0.574 279 0.000084 0.453 280 0.000052 0.073 281 0.000181 0.152282 0.000118 0.486 283 0.000354 0.839 284 0.000288 0.230 285 0.0001070.062 286 0.000155 0.050 287 0.000137 0.050 288 0.000484 0.652 2890.000214 0.131 290 0.000215 0.149 291 0.000083 0.104 292 0.000356 0.399293 0.000242 0.207 294 0.000660 0.687 295 0.000321 0.104 296 0.0002111.310 297 0.000128 0.066 298 0.000279 0.262 299 0.000367 0.456 3000.000165 0.284 301 0.000196 0.141 302 0.000107 0.084 303 0.000150 0.101304 0.000226 0.239 305 0.000330 0.327 306 0.000282 0.246 307 0.0000870.041 308 0.000111 0.070 309 0.000215 0.064 310 0.000117 0.517 3110.000324 0.362 312 0.000576 0.408 313 0.000225 0.131 314 0.000118 0.126315 0.000122 0.124 316 0.000166 0.047 317 0.000186 0.088 318 0.0001380.077 319 0.000081 0.087 320 0.000524 0.302 321 0.000145 0.092 3220.000145 0.087 323 0.000166 0.169 324 0.000136 0.057 325 0.000180 0.192326 0.000307 0.488 327 0.000214 0.174 328 0.000087 0.048 329 0.0001370.243 330 0.000425 0.278 331 0.000184 0.230 332 0.000096 0.089 3330.000088 0.082 334 0.000186 0.159 335 0.000148 0.133 336 0.000085 0.051337 0.000090 0.059 338 0.000100 0.057 339 0.000117 0.153 340 0.0001280.060 341 0.000052 0.042 342 0.000089 0.104 343 0.000093 0.094 3440.000116 0.057 345 0.000803 1.040 346 0.000062 0.066 347 0.000392 0.871348 0.002625 5.360 349 0.001610 7.790 350 0.012333 >33.3 351 0.0001210.196 352 0.000111 0.162 353 0.000135 0.186 354 0.000214 0.450 3550.000172 0.272 356 0.000110 0.367 357 0.000067 0.118 358 0.000066 0.144359 0.002080 >33.3 360 0.001067 2.410 361 0.000101 0.028 362 0.0000610.058 363 0.000080 0.101 364 0.192500 >33.3 365 0.000104 0.032 3660.000248 0.133 367 0.000201 0.273 368 0.000069 0.068 369 — 0.071 370 —0.369 371 0.000101 0.043 372 0.000175 0.085 373 0.000069 0.060 3740.000095 0.041 375 0.000102 0.042 376 0.000152 0.064 377 0.000130 0.055378 0.001187 1.415 379 0.000220 0.235 380 0.000712 0.338 381 0.0001570.262 382 0.000130 0.106 383 0.000194 0.182 384 0.000324 0.266 3850.000762 0.717 386 0.000273 0.211 387 0.000291 0.272 388 0.000069 0.194389 0.000218 0.278 390 0.000095 0.068 391 0.001120 1.710 392 0.0004434.610 393 0.000079 1.590 394 0.000533 0.461 395 0.000302 1.960 3960.000084 1.020 397 0.000532 1.820 398 0.001007 5.585 399 0.000401 2.100400 0.001100 2.872 401 0.002380 2.170 402 0.001399 0.745 403 0.0004720.215 404 0.000565 0.319 405 0.000057 0.018 406 0.000304 0.329 4070.000751 0.567 408 0.000225 4.610 409 0.000214 0.140 410 0.000327 0.247411 0.000930 0.796 412 0.001410 0.749 413 0.000257 0.145 414 0.0001541.840 415 0.000294 4.020 416 0.000423 6.910 417 0.001750 6.320 4180.000662 0.515 419 0.003310 2.140 420 0.000176 0.080 421 0.001175 0.596422 0.000289 0.405 423 0.000269 0.626 424 — 2.240 425 0.000281 0.086 4260.001315 2.170 427 0.000208 0.141 428 0.000154 0.316 429 0.000214 0.174430 0.002475 1.310 431 0.000555 0.206 432 0.000229 0.302 433 0.0011861.670 434 0.000585 0.913 435 0.000380 0.152 436 0.000156 3.200 4370.000201 0.080 438 0.000308 0.230 439 0.000427 0.505 440 0.000140 0.038441 0.000459 0.443 442 0.000221 0.286 443 0.001255 0.555 444 0.0001280.251 445 0.000282 0.161 446 0.000776 0.446 447 0.000119 0.069 4480.000315 0.581 449 0.000449 0.290 450 0.000112 0.791 451 0.001006 1.810452 0.003375 17.200 453 0.000451 0.611 454 0.000174 0.213 455 0.0001040.110 456 0.001045 0.908 457 0.001468 2.610 458 0.000848 0.439 4590.000225 0.267 460 0.000147 0.161 461 0.000111 0.218 462 0.000261 0.198463 0.000439 0.322 464 0.000387 0.426 465 0.000581 0.536 466 0.0009000.446 467 0.000223 0.173 468 0.001075 1.210 469 0.000075 0.295 4700.000156 0.122 471 0.000321 0.943 472 0.000167 0.068 473 0.000112 0.025474 0.000088 0.042 475 0.000411 0.350 476 0.000223 0.173 477 0.0002400.403 478 0.000423 0.197 479 0.000315 4.980 480 0.000067 0.113 4810.000212 1.110 482 0.000180 0.590 483 0.000244 0.260 484 0.000075 0.162485 0.000292 1.210 486 0.000081 0.269 487 0.000221 1.500 488 0.0000760.183 489 0.000035 0.046 490 0.000288 1.860 491 0.000096 0.453 4920.000295 0.516 493 0.000109 0.170 494 0.000276 1.480 495 0.000075 0.082496 0.000105 0.207 497 0.000469 1.210 498 0.000120 0.143 499 0.0003550.110 500 0.000147 0.078 501 0.000672 5.030 502 0.000069 0.191 5030.000331 0.200 504 0.000159 0.087 506 0.003800 7.430 507 0.013700 >33.3508 0.000248 1.130 509 0.000155 0.744 510 0.000258 1.520 511 0.0004931.380 512 0.000170 0.363 513 0.000235 0.383 514 0.000279 0.567 5150.000113 0.120 516 0.000254 0.209 517 0.000259 0.252 518 0.000164 0.224519 0.000157 0.116 520 0.000128 0.095 521 0.000133 0.174 522 0.0001420.110 523 0.000158 0.260 524 — 0.135 525 0.000142 0.087 526 0.0001440.289 527 0.000804 2.190 528 0.000162 0.140 529 0.005565 2.840 5300.001200 0.530 531 0.000141 0.138

TABLE 5 Example Mcl-1 HTRF IC₅₀ OPM-2 10% FBS Number (μM) IC₅₀ IP (μM)100001 0.000055 0.124 100002 0.000071 0.041 100003 0.00042 0.238 1000040.000072 0.120 100005 0.000091 0.062 100006 0.000081 0.131 1000070.000367 0.142 100008 0.000170 0.541 100009 0.000128 0.216 1000100.000077 0.142 100011 0.000153 0.134 100012 0.000275 1.131 1000130.000199 0.068 100014 0.000228 0.330 100015 0.001040 1.003 1000160.000182 0.132 100017 0.000039 0.040 100018 0.000061 0.049 1000190.000182 0.058 100020 0.000032 0.085 100021 0.001053 — 100022 0.000861 —100023 0.003940 — 100024 0.006155 — 100025 0.002348 — 100026 0.002145 —100027 0.007340 — 100028 0.001257 — 100029 0.008733 — 100030 0.010355 —100031 0.007450 — 100032 0.000442 — 100033 0.002815 — 100034 0.000877 —100035 0.000601 1.470 100036 0.000889 1.980 100037 0.001805 1.920 1000380.001655 2.560 100039 0.000563 0.744 100040 0.002745 4.950 1000410.003365 4.990 100042 0.004860 2.220 100043 0.001670 7.280 1000440.031100 7.290 100045 0.000308 0.342 100046 0.003760 0.976 1000470.005150 2.540 100048 0.000187 0.551 100049 0.001261 2.150 1000500.001282 3.824 100051 0.000217 0.502 100052 0.000191 0.424 1000530.000294 0.609 100054 0.004110 9.060 100055 0.001270 4.630 1000560.000424 1.680 100057 0.000568 2.600 100058 0.001760 3.360 1000590.011900 3.450 100060 0.004010 5.980 100061 0.000780 0.529 1000620.004250 9.940 100063 0.002320 2.260 100064 0.002540 3.730 1000650.004855 7.390 100066 0.001430 3.820 100067 0.001009 0.271 1000680.004410 0.765 100069 0.000457 0.250 100070 0.004855 1.070 1000710.001540 0.588 100072 0.000451 1.720 100073 0.000346 1.197 1000740.000731 3.020 100075 0.000671 1.817 100076 0.009655 2.670 1000770.000190 0.052 100078 0.000409 2.720 100079 0.000343 0.713 1000800.000610 0.818 100081 0.007330 5.930 100082 0.000539 0.727 1000830.000179 0.123 100084 0.000745 1.488 100085 0.000245 0.288 1000860.000537 0.390 100087 0.000864 0.187 100088 0.002125 1.340 1000890.000348 0.325 100090 0.000795 0.798 100091 0.001195 1.350 1000920.004015 2.210 100093 0.000291 0.554 100094 0.003835 4.380 1000950.000148 0.113 100096 0.000624 0.517 100097 0.000081 5.230 1000980.000231 0.748 100099 0.000659 0.349 100100 0.002100 1.325 1001010.000062 2.595 100102 0.000990 1.430 100103 0.000325 0.778 1001040.000599 0.250 100105 0.005930 3.660 100106 0.000143 0.121 1001070.000296 0.181 100108 0.000436 0.358 100109 0.000486 2.140 1001100.001480 0.686 100111 0.000352 0.687 100112 0.001295 1.800 1001130.000182 0.070 100114 0.001052 0.491 100115 0.004485 2.840 1001160.003775 5.940 100117 0.002405 3.170 100118 0.004440 3.950 1001190.001720 1.570 100120 0.000067 0.635 100121 0.000056 2.530 1001220.000098 1.190 100123 0.000092 2.660 100124 0.000323 0.270 1001250.000430 0.555 100126 0.000183 0.041 100127 0.000175 0.108 1001280.000089 0.217 100129 0.002400 4.870 100130 0.002690 2.170 1001310.000163 0.144 100132 0.000543 0.675 100133 0.000885 0.984 1001340.000845 3.510 100135 0.000173 0.161 100136 0.000368 0.556 1001370.000365 2.820 100138 0.000549 0.342 100139 0.002585 0.974 1001400.000486 0.299 100141 0.001058 1.370 100142 0.000717 0.663 1001430.001870 3.270 100144 — 0.208 100145 0.000357 0.945 100146 0.0005150.347 100147 0.000305 0.666 100148 0.000113 0.239 100149 0.000214 0.186100150 0.001685 1.430 100151 0.000120 0.071 100152 0.000449 0.377 1001530.000738 4.660 100154 0.001720 1.070 100155 0.000225 0.332 1001560.000410 0.568 100157 0.004810 3.210 100158 0.000298 0.260 1001590.000559 0.591 100160 0.000169 0.078 100161 0.000355 0.757 1001620.003470 2.870 100163 0.002790 1.000 100164 0.000917 0.967 1001650.000455 0.579 100166 0.001765 0.945 100167 0.000377 0.339 1001680.000249 0.196 100169 0.004825 2.270 100170 0.012100 7.820 1001710.000578 0.868 100172 0.001295 1.570 100173 0.000539 0.379 1001740.002025 1.910 100175 0.000149 0.452 100176 0.000480 0.603 1001770.000258 0.259 100178 0.000432 0.237 100179 0.005810 0.840 1001800.004917 4.425 100181 0.000537 0.226 100182 0.000863 0.827 1001830.001340 2.245 100184 0.000717 0.179 100185 0.008883 5.130 1001860.000377 0.312 100187 0.002760 3.110 100188 0.000877 0.735 1001890.000820 0.701 100190 0.004790 2.480 100191 0.001600 0.557 1001920.000192 0.149 100193 0.000856 1.300 100194 0.000613 0.619 1001950.001075 0.625 100196 0.000461 0.358 100197 0.000774 2.460 1001980.000307 0.399 100199 0.000166 0.148 100200 0.000213 1.070 1002010.000086 0.307 100202 0.000352 0.928 100203 0.000285 0.491 1002040.001655 5.270 100205 0.000206 0.068 100206 0.001260 1.750 1002070.000141 0.215 100208 0.000431 0.318 100209 0.002675 3.380 1002100.003475 3.360 100211 0.001435 4.780 100212 0.000901 1.620 1002130.002845 2.020 100214 0.000143 0.095 100215 0.000595 1.250 1002160.000311 0.374 100217 0.000183 0.130 100218 0.000621 0.675 1002190.000401 0.974 100220 0.007415 6.840 100221 0.000525 0.776 1002220.000182 0.222 100223 0.001410 2.150 100224 0.000345 0.385 1002250.000639 0.882 100226 0.001395 0.849 100227 0.000423 0.191 1002280.000558 3.300 100229 0.000356 1.490 100230 0.000473 0.544 1002310.000312 0.350 100232 0.000152 0.389 100233 0.001040 0.257 1002340.000237 0.449 100235 0.001345 0.644 100236 0.001096 0.933 1002370.001740 0.996 100238 0.000474 0.747 100239 0.000333 3.740 1002400.000385 0.266 100241 0.000365 0.401 100242 0.002145 1.450 1002430.011500 8.670 100244 0.000182 0.049 100245 0.001715 1.980 1002460.000326 0.114 100247 0.000542 0.624 100248 0.011050 6.680 1002490.002995 2.270 100250 0.000136 0.082 100251 0.003290 3.730 1002520.000112 0.077 100253 0.000149 0.544 100254 0.004070 2.150 1002550.014450 5.020 100256 0.005040 1.200 100257 0.000180 0.080 1002580.000553 0.519 100259 0.006180 1.250 100260 0.000408 0.094 1002610.001220 0.533 100262 0.000134 0.433 100263 0.001830 3.390 1002640.000384 0.600 100265 0.000439 0.441 100266 0.000292 0.571 1002670.000166 0.274 100268 0.003440 3.810 100269 0.000908 1.230 1002700.000776 3.72 100271 0.002480 6.120 100272 0.000401 0.349 1002730.005655 8.660 100274 0.000377 0.543 100275 0.000113 0.309 1002760.000326 1.528 100277 0.000266 0.448 100278 0.000458 0.333 1002790.000777 3.25 100280 0.000368 0.305 100281 0.000117 0.352 1002820.000268 1.280 100283 0.000143 0.806 100284 0.000285 0.396 1002850.000241 0.642 100286 0.000471 1.580 100287 0.000494 1.870 1002880.000103 0.089 100289 0.000878 3.960 100290 0.000116 0.259 1002910.000137 0.281 100292 0.000115 0.672 100293 0.000522 0.726 1002940.000118 0.116 100295 0.000279 0.302 100297 0.000115 0.168 1002980.000140 0.199 100299 0.000350 0.623 100300 0.000109 0.235 1003010.001315 1.930 100302 0.003805 4.880 100303 0.003640 7.330 1003040.000311 0.464 100305 0.000473 1.140 100306 0.000124 0.278 1003070.000049 1.030 100308 0.000033 1.170 100309 0.000244 0.385 1003100.000152 0.120 100311 0.001030 1.190 100312 0.000088 0.234 1003130.000129 0.143 100314 0.002925 2.290 100315 0.000200 0.153 1003160.000276 0.375 100317 0.000188 0.157 100318 0.000095 0.114 1003190.000126 0.506 100320 0.001200 2.140 100321 0.000209 0.285 1003220.00223 1.54 100323 0.000477 1.250 100324 0.000244 1.170 100325 0.0001820.482 100326 0.000615 0.334 100327 0.000295 0.550 100328 0.000261 0.180100329 0.005023 1.560 100330 0.000083 8.260 100331 0.000192 8.260 1003320.006465 4.31 100333 0.002100 2.170 100334 0.003273 1.470 1003350.000319 0.165 100336 0.001123 1.810 100337 0.001608 2.410 1003380.000502 1.920 100339 0.000186 1.380 100340 0.000779 0.308 100341 0.00411.94 100342 0.001685 0.782 100343 0.002510 0.617 100344 0.000309 0.290100345 0.002420 0.218 100346 0.000735 0.248 100347 0.000689 1.080 1003480.000135 0.125 100349 0.00115 0.058 100350 0.000489 0.554 1003510.000115 2.02 100352 0.002750 0.246 100353 0.000348 0.151 1003540.000109 0.147 100355 0.000535 0.776 100356 0.000084 0.071 1003570.000224 0.399 100358 0.000118 0.081 100359 0.001200 1.540 1003600.000848 1.230 100361 0.000208 0.155 100362 0.000888 2.1 100363 0.0013833.810 100364 0.001160 1.680 100365 0.000257 0.245 100366 0.000198 0.168100367 0.000371 0.604 100368 0.000377 0.611 100369 0.00283 9.92 1003700.000153 0.258 100371 0.00039 0.307 100372 0.000165 0.833 1003730.000318 0.736 100374 0.000289 0.433 100375 0.000070 0.176 1003760.000150 0.362 100377 0.000107 0.182 100378 0.000037 0.111 1003790.000060 0.071 100380 0.000208 0.137 100381 0.000328 2.910 1003820.000471 0.312 100383 0.000264 3.430 100384 0.000821 0.729 1003850.000144 0.144 100386 0.004017 7.27 100387 0.000175 3.760 1003880.001167 2.160 100389 0.000101 0.114 100390 0.000186 0.649 1003910.000441 0.282 100392 0.000112 0.129 100393 0.000164 0.211 1003940.000242 0.622 100395 0.000056 0.040 100396 0.000272 1.470 1003970.000198 0.404 100398 0.000618 0.457 100399 0.000280 2.810 1004000.000838 1.320 100401 0.001797 8.390 100402 0.000098 0.133 1004030.000226 0.39 100404 0.002553 8.15 100405 0.000545 1.120 100406 0.0003600.747 100407 0.000278 0.516 100408 0.001353 5.62 100409 0.000124 0.206100410 0.000127 0.297 100411 0.000584 2.1 100412 0.000097 0.249 1004130.000228 0.556 100414 0.000626 1.270 100415 0.001950 2.285 1004160.000092 0.086 100417 0.000345 0.379 100418 0.000098 0.141 1004190.000277 0.416 100420 0.000112 0.161 100421 0.003926 4.93 1004220.000174 0.182 100423 0.000056 0.099 100424 0.000249 0.469 1004250.000165 0.717 100426 0.000197 0.110 100427 0.000209 0.342 1004280.000210 0.218 100429 0.000176 1.420 100430 0.000057 0.358 1004310.000043 0.290 100432 0.000228 0.711 100433 0.000026 0.296 1004340.000162 0.482 100435 0.000055 0.305 100436 0.000076 0.335 1004370.000073 0.531 100438 0.000169 0.547 100439 0.000619 2.640 1004400.000398 0.354 100441 0.000133 0.154 100442 0.000921 3.870 1004430.000070 0.156 100444 0.000098 0.646 100445 0.000040 0.098 1004460.000126 0.345 100447 0.000050 0.184 100448 0.000373 1.920 1004490.000071 0.171 100450 0.000336 1.910 100451 0.000111 0.412 1004520.000077 0.157 100453 0.000927 2.930 100454 0.000652 0.802 1004550.000087 0.140 100456 0.000565 1.230 100457 0.000331 0.967 1004580.000210 0.418 100459 0.000685 0.732 100460 0.000095 0.433 1004610.000042 0.382 100462 0.000304 0.652 100463 0.000383 1.130 100464 —1.530 100465 0.000121 0.729 100466 0.000043 1.440 100467 0.000303 0.516100468 0.000393 0.943 100469 0.000085 0.325 100470 0.000576 9.65 1004710.000281 0.299 100472 0.000651 0.357 100473 0.000974 0.178 1004740.000405 0.387 100475 0.001365 2.710 100476 — 1.340 100477 0.0003130.159 100478 0.003470 4.090 100479 0.000758 0.332 100480 0.000176 0.221100481 0.000094 0.152 100482 0.000183 0.105 100483 0.001664 1.690 1004840.003850 3.370 100485 0.000192 0.272 100486 0.000381 0.102 1004870.000436 0.340 100488 0.000389 0.346 100489 0.000880 0.182 1004900.000292 0.511 100491 0.000208 0.308 100492 0.000749 0.436 1004930.000322 0.512 100494 0.000078 0.089 100495 0.000462 0.539 1004960.002665 5.060 100497 0.000064 0.106 100498 0.000885 1.660 1004990.000509 1.120 100500 0.000049 0.071 100501 0.000090 0.518 1005020.000290 0.393 100503 0.000493 0.706 100504 0.000803 1.890 1005050.000165 0.137 100506 0.000497 1.270 100507 0.000430 0.490 1005080.002734 2.500 100509 0.000057 0.361 100510 0.000070 0.379 1005110.000070 0.430 100512 0.000415 1.490 100513 0.000071 0.288 1005140.000088 0.231 100515 0.000132 0.585 100516 0.003360 1.900 1005170.001059 3.460 100518 0.000427 0.668 100519 0.000175 0.138 1005200.000549 1.690 100521 0.000197 0.296 100522 0.000144 0.538 1005230.000812 0.622 100524 0.000990 0.842 100525 0.003305 1.430 1005260.000387 0.826 100527 0.003595 3.570 100528 0.000138 0.257 1005290.000287 0.245 100530 0.000171 0.448 100531 0.000083 0.172 1005320.000053 8.637 100533 0.008565 3.990 100534 0.000799 0.542 1005350.000570 0.964 100536 0.000204 0.826 100537 0.000115 0.256 1005380.001470 2.400 100539 0.000144 0.727 100540 0.000275 0.320 1005410.000760 0.826 100542 0.000229 0.902 100543 0.000451 0.821 1005440.000171 0.306 100545 0.000153 0.231 100546 0.000084 0.440 1005470.000031 1.860 100548 0.000064 8.410 100549 0.002570 0.545 1005500.000059 6.859 100551 0.000174 0.142 100552 0.000065 0.957 1005530.001040 2.790 100554 0.000231 0.519 100555 0.000101 0.113 1005560.000113 0.734 100557 0.000093 0.299 100558 0.000086 0.274 1005590.000113 1.030 100560 0.000041 2.020 100561 0.000275 0.673 1005620.000057 0.532 100563 0.000065 0.510 100564 0.000333 1.430 1005650.001540 2.060 100566 0.000142 0.590 100567 0.000125 0.249 1005680.000431 1.540 100569 0.002479 2.000 100570 0.003380 5.050 1005710.000076 0.922 100572 0.000174 1.160 100573 0.002070 7.390 1005740.001420 4.320 100575 0.001300 2.500 100576 0.001150 4.090 1005770.000045 2.020 100578 0.000089 0.595 100579 0.000214 0.757 1005800.000877 6.580 100581 0.000363 1.540 100582 0.000197 1.120 1005830.000124 0.411 100584 0.000139 0.349 100585 0.000057 0.696 1005860.000074 0.453 100587 0.000136 0.177 100588 0.000075 0.117 1005890.001835 3.330 100590 0.000086 0.501 100591 0.000075 0.060 1005920.000275 0.139 100593 0.000464 0.215 100594 0.000143 0.241 1005950.000157 0.133 100596 0.000229 0.186 100597 0.000263 0.577 1005980.000077 0.188 100599 0.001150 1.140 100600 0.000445 0.528 1006010.000114 0.239 100602 0.000800 2.330 100603 0.000651 1.570 1006040.000723 4.110 100605 0.003245 7.950 100606 0.000209 0.428

In-Vivo Data

Tumor Pharmacodynamics (PD)

FIGS. 1-7 illustrate the PD results of the cited Examples. The ReferenceCompound 1, an internal Amgen MCl-1 inhibitor compound made by one ofthe general schemes outlined in U.S. Pat. No. 9,562,061, hereinincorporated by reference, is(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one13′,13′-dioxide

Female Athymic nude (Charles River Laboratories, Inc., Hollister Calif.)mice were inoculated subcutaneously with 5×10⁶ OPM-2 Luc cells. Whentumors reached 300-500 mm³ in size, mice were randomized into treatmentgroups and harvested 6 hours post single dose of compound at variousconcentrations. Tumor lysates were analyzed for active Bak using asandwich ELISA format (Active Bak MSD plate cat #N₄₅ZA-1; Bak detectionantibody Abcam Cat# Ab53153 and Sulfo-Tagged by MSD) and read on a MSDreader (S16000). Columns (n=3 per group) represent level of luminescence(cps). Statistical significance was determined by Oneway ANOVA followedby Dunnett's post hoc compared to the vehicle control group. Blackdiamonds represent drug plasma concentration and circles represent drugconcentration in the tumor.

OPM-2 Xenograft

Examples 8-13 illustrate Xenograft data of various compounds of thepresent invention. Female Athymic nude (Charles River Laboratories,Inc., Hollister Calif.) mice were inoculated subcutaneously with 5×10⁶OPM-2 Luc cells. When average tumor volumes reached approximately155-183 mm³, animals were randomized (n=10/group) and dosed once dailyby oral gavage (10-12 days) with test compounds at variousconcentrations unless notes otherwise. Tumor volume and body weightswere recorded twice per week using electronic calipers and an analyticalscale. Statistical analysis was performed using Repeated Measures ANOVA(RMANOVA) followed by Dunnett's post-hoc analysis.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended Claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

The invention claimed is:
 1. A method of treating cancer, the methodcomprising: administering to a patient in need thereof, atherapeutically effective amount of a compound, a stereoisomer thereof,a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable salt of the stereoisomer thereof, wherein the cancer is ahematologic malignancy and further wherein the compound is selectedfrom:


2. The method of claim 1, wherein the compound or the pharmaceuticallyacceptable salt thereof is administered to the patient.
 3. A method oftreating cancer, the method comprising: administering to a patient inneed thereof, a therapeutically effective amount of a compound, astereoisomer thereof, a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable salt of the stereoisomer thereof, whereinthe cancer is selected from the group consisting of breast cancer,colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer,lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin'slymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenousleukemia, and further wherein the compound is selected from:


4. The method of claim 1, wherein the cancer is multiple myeloma.
 5. Themethod of claim 1, wherein the cancer is acute myelogenous leukemia. 6.The method of claim 1, wherein the cancer is non-Hodgkin's lymphoma. 7.The method of claim 1, further comprising administering to the patientin need thereof a therapeutically effective amount of an additionalpharmaceutically active compound.
 8. The method of claim 7, wherein theadditional pharmaceutically active compound is carfilzomib.
 9. Themethod of claim 7, wherein the additional pharmaceutically activecompound is venetoclax.
 10. The method of claim 7, wherein theadditional pharmaceutically active compound is cytarabine.
 11. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


12. The method of claim 11, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 13. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


14. The method of claim 13, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 15. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


16. The method of claim 15, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 17. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


18. The method of claim 17, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 19. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


20. The method of claim 19, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 21. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


22. The method of claim 21, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 23. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


24. The method of claim 23, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 25. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


26. The method of claim 25, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 27. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


28. The method of claim 27, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 29. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


30. The method of claim 29, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 31. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


32. The method of claim 31, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 33. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


34. The method of claim 33, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 35. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


36. The method of claim 35, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 37. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


38. The method of claim 37, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 39. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


40. The method of claim 39, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 41. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


42. The method of claim 41, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 43. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


44. The method of claim 43, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.
 45. Themethod of claim 1, wherein the compound or the pharmaceuticallyacceptable salt is administered to the patient, and the compound is


46. The method of claim 45, wherein the cancer is selected from multiplemyeloma, acute myelogenous leukemia, or non-Hodgkin's lymphoma.